HU219343B - Process for producing acylated arylalkylamine derivatives and pharmaceutical compositiions comprising them - Google Patents

Abstract

The present invention relates to compounds of formula (I), in free or salt form, having an angiotensin-II antagonist activity, wherein R1 is lower alkyl or lower alkenyl; X 1 = CO, = SO 2 or -O-C (= O) -, wherein the carbon atom of the carbonyl group is attached to the nitrogen atom indicated in the compound of formula (I); X 2 is C 1 -C 10 alkylene or C 2 -C 10 alkylene optionally substituted with hydroxy, carboxy, amino, guanidino, C 3 -C 7 cycloalkyl or imidazolyl optionally substituted by phenyl, optionally substituted by halogen; - or a carbon atom of a C 2 -C 10 alkylene group may additionally be bridged with a C 2 -C 6 alkylene group; or represents a cycloalkylene group having from 3 to 7 carbon atoms, R2 is a carboxyl group optionally esterified with an alcohol containing a lower alkyl or a phenyl lower alkyl group, a phenyl-lower alkyl group optionally mono- or disubstituted with a lower alkyl group or optionally substituted by a hydroxy group; morpholinocarbonyl, C3-7 alkyleneiminocarbonyl, tetrahydroquinol-1-ylcarbonyl, tetrahydroisoquinol-2-ylcarbonyl, lower alkanoylamino, hydroxy, lower alkoxy, phenyl - (lower) alkoxy or phenoxy; X3 lower alkylene; R3 is carboxy or 5-tetrazolyl; and Ring A is optionally further substituted by halogen, and the lower groups have up to 7 carbon atoms and the lower alkenyl groups have from 2 to 7 carbon atoms. The invention further relates to a process for the preparation of a pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt thereof. ŕ

Description

The present invention relates to a process for the preparation of compounds of formula (I), in free or salt form

R 1 is lower alkyl or lower alkenyl;

X 1 = CO, = SO ₂ or -OC (= O) - wherein the carbon atom of the carbonyl group is attached to the nitrogen atom indicated in the compound of formula (I); X _{2 is} C 1 -C 10 alkylene or C 2 -C 10 alkylidene optionally substituted by hydroxy, carboxy, amino, guanidino, C 3 -C 7 cycloalkyl or imidazolyl optionally substituted by phenyl, optionally substituted by halogen; in addition, a carbon atom of an alkylene or C2-C10 alkylidene group may be further bridged with a C2-C6 alkylene group; or represents a C3-C7 cycloalkylene group,

R _{2 is} a carboxyl group optionally esterified with an alcohol containing a lower alkyl or phenyl lower alkyl group, a carbamoyl group optionally substituted with a lower alkyl group mono- or disubstituted or optionally substituted with a hydroxy group; morpholinocarbonyl, C3-C7 alkyleneimino-carbonyl, tetrahydroquinol-1-ylcarbonyl, tetrahydroisoquinol-2-ylcarbonyl, lower alkanoylamino, hydroxy, lower alkoxy, phenyl, lower alkoxy or phenoxy;

X ₃ lower alkylene;

R _{3 is} carboxy or 5-tetrazolyl; and ring A is optionally even substituted with halogen.

The invention further relates to a process for the preparation of a pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt thereof.

The compounds of formula (I) are mainly available in the form of their pharmaceutically acceptable salts. When the compounds of formula I contain at least one basic group, they may form acid addition salts. For example, the salt formation may be carried out with strong inorganic acids such as mineral acids such as sulfuric acid, a phosphoric acid or a hydrohalic acid, strong organic carboxylic acids such as C 1-4 alkanecarboxylic acids optionally substituted with halogen, such as acetic acid, e.g. such as oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acids, hydroxycarboxylic acids such as ascorbic, glycolic, lactic, malic, tartaric or citric acids, and amino acids such as aspartic or glutamic acids, or, for example, benzoic acid or organic sulfonic acids, such as C1 -C4 alkanesulfonic or arylsulfonic acids optionally substituted with halogen, such as methane or ptoluenesulfonic acid. Suitable acid addition salts may also be formed with an additional basic group, if present. Compounds of formula (I) containing at least one acidic group (e.g., COOH or 5-tetrazolyl) may form salts with bases. Suitable bases include, for example, metal salts such as alkali metal or alkaline earth metal salts such as sodium, potassium or magnesium salts, or with ammonia or an organic amine such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono- or di- - lower alkylamine such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a mono-, di- or trihydroxy (lower) salts with alkylamine such as mono-, di- or triethanolamine. In addition, suitable internal salts may be formed. These salts also include pharmaceutically unacceptable salts, which are useful, for example, in the isolation or purification of the free compounds of formula (I) or their pharmaceutically acceptable salts.

In the foregoing and following, the following general definitions shall have the following meanings, unless otherwise specified:

The term "lower" means that the corresponding groups and compounds contain up to 7, preferably up to 4, carbon atoms.

The term "halogen" means mainly halogen of up to 35 atoms, such as fluorine, chlorine or bromine, and also includes iodine.

A lower alkyl group is a C 1-7 alkyl group such as methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the meaning includes it also includes the corresponding pentyl, hexyl and heptyl groups. C 1-4 alkyl groups are preferred. Lower alkenyl groups have from 2 to 7 carbon atoms.

Cycloalkyl means a C3-C7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Of these groups, cyclopentyl and cyclohexyl are preferred.

The phenyl (lower) alkyl group is preferably a phenyl (C 1 -C 4) alkyl group, and most preferably benzyl, 1- and 2-phenethyl.

The alkylene group is preferably a straight or branched C 1 -C 7 alkylene group, especially methylene, ethylene, propylene and butylene, and

1,2-propylene, 2-methyl-1,3-propylene and 2,2-dimethyl-1,3-propylene. C 1-5 alkylene is preferred.

The alkylidene group is a C 2 -C 10 alkylidene group, such as ethylidene or 2,2-propylidene, and 1,1- or 2,2-butylidene or 1,1-,

2.2- or 3,3-pentylidene. C2-C5 alkylidene is preferred.

Cycloalkylene is a C3-C7 cycloalkylene group and is, for example, 1,2-cyclopropylene, 1,2- or

1,3-cyclobutylene, 1,2-, 1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene and 1,2-, 1,3- or 1,4-cycloheptylene. 1,3-cyclopentylene and 1,4-cyclohexylene are preferred.

The state of the art does not include information on the compounds of the present invention

EN 219 343 Β. EP 148 752 and EP 253 310, for example, disclose classes of compounds which are clearly structurally distinct from compounds of formula (IK).

Extensive pharmacological studies have shown that the compounds of formula I and their pharmaceutically acceptable salts, for example, possess pronounced angiotensin II antagonist properties.

Angiotensin-II is known to have a strong vasoconstrictive property and, in addition, to stimulate aldosterone secretion, thereby causing significant sodium / water retention. Angiotensin-II activity results, inter alia, in an increase in blood pressure. The importance of angiotensin-II antagonists is to suppress angiotensin-II-induced vasoconstrictor and aldosterone-stimulating effects by competitively inhibiting angiotensin-II receptor binding.

The angitensin II antagonist properties of the compounds of formula (I) and their pharmaceutically acceptable salts can be understood in the angiotensin II binding assay. To do this, rat smooth muscle cells from homogenized rat aorta were used. The solid supernatant was resuspended in 50 mM Tris buffer (pH 7.4) with the addition of peptidase inhibitors. Samples were incubated with ¹²⁵ Iangiotensin II (0.175 nM) at 25 ° C for 60 minutes, varying in concentration of angiotensin II or test substance. The incubation was then terminated with ice cold phosphate buffered sodium chloride and filtered through a Whatman GF / F filter. The filter is counted with a gamma counter. From the dose-response curve, IC ₅₀ values are determined. Compounds of formula (I) and their pharmaceutically acceptable salts have IC ₅₀ values of about 10 nM or more.

Angiotensin II-induced vasoconstriction was determined using rabbit aortic ring experiments. For each experiment, each aortic ring isolated from the chest was prepared and fixed with an initial tension of 2 g between two parallel forceps. The rings were then immersed at 37 ° C in 20 ml of tissue roll and treated with a gas mixture containing 95% O ₂ and 5% CO ₂ . Isometric reactions were measured. At 20 minute intervals, rings were stimulated alternately with 10 nM angiotensin (HypertensinClBA) and 5 nM noradrenaline chloride. The rings were then incubated with a specific concentration of test substance prior to treatment with the agonist. Data were analyzed with a Buxco digital computer. Concentrations that inhibited baseline control values by 50% were reported as IC ₅₀ values. The compounds of formula (I) and their pharmaceutically acceptable salts have an IC _{50 of 5} nM or more.

The ability of the compounds of formula (I) and their pharmaceutically acceptable salts to reduce angiotensin-II-induced hypertension can be demonstrated in experiments in normotensive, narcotic rats. After calibration of the preparations with 0.9% sodium chloride (1 ml / kg iv), noradrenaline (1 pg / kg iv) or angiotensin II (0.3 pg / kg iv), the test substance increasing doses (3-6) are administered intravenously, with angiotensin II and noradrenaline being administered at 5-minute intervals thereafter. Blood pressure was measured directly in the carotid artery and recorded using an online data processing system (Buxco). The angiotensin-II antagonist effect is manifested in the selective inhibition of angiotensin-II and not in the inhibition of the pressure effect caused by noradrenaline. In this body model, the compounds of formula I and their pharmaceutically acceptable salts exhibit inhibitory activity at concentrations of 0.3 mg / kg or more when administered intravenously.

The antihypertensive activity of the compounds of formula (I) and their pharmaceutically acceptable salts is also evident in studies in renally hypertensive rats. In male rats, a Goldblatt method of narrowing a renal artery produces high blood pressure. In rats, the test substance is administered by gavage. Control animals received an equivalent volume of solvent. Blood pressure and heart rate in animals that are awake indirectly, by tail clip, by Gerold et al., Helv. Physiol. Acta 24 (1966), 58] is measured before the test substance or solvent is added and at intervals throughout the experiment. The marked antihypertensive effect is about 30 mg / kg p.o. dose.

Accordingly, the compounds of formula (I) and their pharmaceutically acceptable salts are useful as antihypertensive agents, for example in the treatment of hypertension and heart failure. Accordingly, the present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hypertension and heart failure. The preparation of pharmaceutical compositions also includes the commercial manufacture of active ingredients.

The present invention relates in particular to processes for the preparation of compounds of formula Ia and salts thereof wherein R _b X _b X ₂ , R ₂ are as defined above, and ring A is optionally substituted with halogen.

This invention relates in particular to processes for the preparation of compounds of formula Ia and salts thereof wherein X _{2 is} lower alkylene or lower alkylidene optionally substituted with hydroxy or 3-7 membered cycloalkyl, wherein the lower alkylene and a carbon atom of a C 1-4 alkylidene group may be bridged with 2-6, especially C 4-5 alkylene groups, or wherein X _{2 is a C} 3-7 cycloalkylene group, R 1, X _b R ₂ and r ₃ are as defined above and rings A and B are they may be substituted as above.

The present invention therefore relates to a process for the preparation of the compounds of the invention. The compounds of formula (I) and their salts are prepared in a manner known per se by (a) reacting a compound of formula (II) or a salt thereof, wherein Z 1 is a functionally modified carboxy

Converting EN 219 343 Β group Z, the group _R3-COOH, or (b) a compound (II) or a salt thereof, if Zj is a protected 5-tetrazolyl, Z ₃ still another aspect deprotected converted to R ₃ 5-tetrazolyl or (c) reacting a compound of formula (II) or a salt thereof, if Zj is cyano, Z _r is reacted with an azide is converted to R ₃ 5-tetrazolyl, or (d) a compound (I) or a salt thereof the preparation of which R ₂ is a carboxy group in a compound of formula (I) wherein R ₂ is an esterified carboxy group, the ester is decomposed, (e) to produce a compound of formula (I) or a salt thereof wherein R ₂ is an esterified carboxy group, (f) preparing a compound of formula (I) or a salt thereof, wherein R ₂ is carboxy; n R ₂ is an amidated carboxyl group, an amidation of a compound of formula I wherein R ₂ is a carboxy group, (g) to produce a compound of formula I or a salt thereof wherein R ₂ is a hydroxymethyl group with X ₂ , a compound of formula (I) wherein R ₂ is an optionally esterified carboxy group, is reduced with a suitable reducing agent (h) or a compound of formula (I) or a salt thereof wherein R ₂ is a hydroxymethyl group with a methylene group of X ₂ , in a compound of formula (I) wherein R ₂ is an etherified hydroxy group, the ether is decomposed and, if desired, a free base of a compound of formula (I) prepared according to the invention or a compound of formula (I) A compound of formula (I) or another salt We converted.

R can be converted into ₃ groups Z, groups such as cyano, mercapto group, a halogen atom, the -N 2 + A 'group, wherein A represents a deduced acid anion, an amino group, and a, COOH, SO ₃ H, PO ₃ A functionally formed group other than H ₂ or PO ₂ H ₂ and an N-protected 5-tetrazolyl group.

The reactions mentioned above and thereafter in the process variants are known in the art, for example, in the absence or in the presence of a suitable solvent or diluent or mixture thereof, if necessary under reflux, room temperature or heating, e.g. preferably in the temperature range of about -10 ° C to about + 200 ° C, and if necessary under pressure in an inert gas atmosphere and / or under anhydrous conditions.

the)

Examples of Z 1 which can be converted to R _{3 to a} 5-tetrazolyl group are cyano or a protected 5-tetrazolyl group.

For the preparation of compounds of formula I wherein R _{3 is} 5-tetrazolyl, the starting materials of formula II wherein Z _{3 is} cyano and these compounds with an azide such as HN ₃ or mainly a salt thereof are used. for example, an alkali metal salt or an organic tin azide such as tri- (lower) alkyl or triaryl tin azide. Preferred azides are, for example, sodium or potassium azide and tri-lower alkyl such as triethyl. - or tributyltin azide and triphenyltin azide. For the formation of the 5-tetrazolyl group, it is preferable to react with starting materials of the formula (II) in which R _{2 is} other than carboxy.

Suitable protecting groups for protected tetrazolyl groups include those conventionally used in tetrazolyl chemistry, especially triphenylmethyl, and optionally substituted nitro, such as 4-nitrobenzyl, and a lower alkoxymethyl such as methoxy or ethoxy. methyl, lower alkylthiomethyl such as methylthiomethyl, silyl groups such as tri-lower alkylsilyl groups such as dimethyl tert-butyl and triisopropylsilyl as well as 2-cyanoethyl and lower alkoxy (lower) alkoxy groups such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl.

Cleavage of the protecting groups is carried out according to known methods, such as described by J. Green in Protective Groups in Organic Synthesis, Wiley-Interscience (1980). For example, the triphenylmethyl group is hydrolyzed, in particular in the presence of an acid; for example, hydrogenation of the 4-nitrobenzyl group in the presence of a hydrogenation catalyst; a methoxy or ethoxymethyl group, for example, with a tri-lower alkyl such as triethyl or tributyltin bromide; treating the methylthiomethyl group with, for example, trifluoroacetic acid; silyl groups such as fluorides such as tetra-lower alkylammonium fluorides such as tetrabutylammonium fluoride or alkali metal fluorides such as sodium fluoride or 2-cyanoethyl group such as hydrolysis, for example, by hydrolysis with sodium hydroxide solution; hydrolysis of the 2-methoxyethoxymethyl group by hydrolysis such as hydrochloric acid; the benzyloxymethyl group and the phenacyl group may be cleaved, for example, by hydrogenation in the presence of a hydrogenation catalyst.

Z, which is convertible to R ₃ -COOH, is a functionally formed carboxy group, such as a cyano group, an esterified or amidated carboxy group, or a hydroxymethyl group.

Preferred functionalized carboxy groups are, for example, a lower alkoxycarbonyl group such as methoxy or ethoxycarbonyl, a tri- (C 1-4) alkylsilyl- (C 1-4) alkoxycarbonyl group. a group, in particular a trimethylsilyl ethoxycarbonyl group or a cyano group. Compounds of formula I wherein R _{3 is a} carboxy group are derived from compounds of formula II

EN 219 343 Β, where Z is a carboxyl group functionally formed as above. The reaction is carried out in a manner known per se, for example by hydrolysis, in particular in the presence of a base, in the case of the corresponding tri-C 1-4 -alkylsilyl-C 1-4 -alkoxycarbonyl derivatives such as ammonium fluoride, e.g. - by treatment with a lower alkyl ammonium fluoride such as tetra-n-butyl ammonium fluoride or, in the case of benzyloxycarbonyl derivatives, by hydrogenation in the presence of a hydrogenation catalyst or starting from compounds of the formula II, in which Z 1 represents hydroxymethyl or formyl group by oxidation using conventional oxidizing agents.

Bases used in the process include, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, di- (lower) alkylamides, aminoaminoalkylamides or - (lower) alkyl- silylamides, naphthalenamines, lower alkylamines, basic heterocyclyenes, ammonium hydroxides, and carbocyclic amines. The following bases may be mentioned as examples: sodium hydroxide, hydride, amide, sodium methylate, ethylate, potassium tert-butylate, carbonate, lithium triphenylmethylide, diisopropylamide, potassium 3- (aminopropyl). amide, bis (trimethylsilyl) amide, dimethylaminaphthalene, di- or triethylamine, or ethyldiisopropylamine, N-methylpiperidine, pyridine, benzyltrimethylammonium hydroxide, 1,5-diaza- bicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

The starting materials of the formula (II) may be prepared by reacting a compound of the formula R ₂ -X ₂ -NH ₂ (Ha) - wherein Z _{2 is} a group -X ₃ -Z ₄ and Z _{4 is a} reactive esterified hydroxy group (-). The compound (IIb) is reacted and the compound (IIc) thus obtained is reacted in the next step in a similar manner to that described in process (a) to (f).

The reactive esterified hydroxy group is mainly a hydroxy group esterified with a strong inorganic acid or an organic sulfonic acid, such as a halogen such as chlorine, bromine or iodine, a sulfonyloxy group such as a hydroxysulfonyloxy group, a halosulfonyloxy group such as fluorine. a sulfonyloxy group, for example a C 1 -C 7 alkanesulfonyloxy group optionally substituted by halogen, such as methane or trifluoromethanesulfonyloxy group, a C 5 -C 7 cycloalkane sulfonyloxy group such as cyclohexane sulfonyloxy; oxy, or benzenesulfonyloxy optionally substituted with, for example, C 1 -C 7 alkyl or halogen, such as p-bromobenzene or ptoluenesulfonyloxy.

Compounds of formula IIb are known, for example, from EP 253 310 or may be prepared by methods known per se. Compounds of formula (IIa) are known in the art or may be prepared in a manner analogous to known processes.

A compound of the invention containing a hydroxy group may be etherified by methods known per se. The etherification may be carried out with an alcohol, such as an optionally substituted lower alkanol or a reactive ester thereof. Reactive esters of the desired alcohol include, for example, esters with strong inorganic or organic acids, such as the corresponding halides, sulfates, lower alkanesulfonates or optionally substituted benzenesulfonates, such as chlorides, bromides, iodides, methane, benzene or p-toluenesulfone. . The etherification may be carried out in the presence of a base such as an alkali metal hydride, hydroxide, carbonate or an amine. Conversely, suitable ethers include, for example, lower alkoxy compounds, for example, strong acids, such as mineral acids, such as halogen acids, such as bromine or iodine, preferably in the form of pyridinium halides, or Lewis acids, e.g.

III. or by treatment with halides of the elements of the corresponding secondary groups. These reactions are carried out, if necessary, with cooling or heating, for example, at a temperature in the range of about -20 ° C to about 100 ° C, with or without a solvent or diluent, in an inert gas atmosphere and / or pressure and optionally in a sealed vessel.

In the compounds of formula (I) which contain an esterified or amidated carboxy group as a substituent, such a group may be converted, for example, by hydrolysis, such as hydrolysis in the presence of a basic or acidic agent such as a mineral acid. Further, the tert-butyloxycarbonyl group can be converted into the free carboxyl group, for example, by treatment with trihalogen, e.g. trifluoroacetic acid, and the benzyloxycarbonyl group, for example, by hydrogenation in the presence of a hydrogenation catalyst, for example.

Further, in the compounds of the formula I having a carboxy group as a substituent, especially when it is not R ₃ , it is an esterifying agent, for example an alcohol such as an inorganic or organic acid or a Lewis in the presence of an acid such as zinc chloride or a water-binding condensing agent such as a carbodiimide such as N, N'-dicyclohexylcarbodiimide or treated with a diazoric reagent such as a diazo- (lower) alkane such as diazomethane to form an esterified carboxy group. The same result can be achieved when the compounds of the formula I containing the carboxy group in free form or in salt form, for example in the form of an ammonium or metal salt such as an alkali metal such as sodium or potassium, are a C 1-7 alkyl halide such as methyl or a reactive ester of ethyl bromide or iodide or an organic sulfonic acid ester, for example, a suitable C 1 -C 7 alkyl ester such as methanesulfonic acid or p-toluenesulfonic acid methyl ester or ethyl ester.

Compounds of formula I which contain, for example, an alcohol esterified carboxy group

EN 219 343 Β, usually with an appropriate alcohol having a higher carbon number than the esterified carboxy group in the starting material, a suitable transesterification agent such as a basic material such as an alkali metal (C 1 -C 7) alkanoate, (C 1 -C 7) alkanolate or cyanide, such as sodium acetate, methanolate, ethylate, tert-butanolate or cyanide, or a suitable acidic agent, optionally by transesterification with continuous removal of the alcohol formed, for example by distillation, to another ester of formula (I). It is also possible to start from the so-called activated esters of the corresponding compounds of formula (I) which contain an active esterified carboxy group (see below) and convert it to another ester by treatment with a C 1-7 alkanol.

Compounds of formula (I) which contain a carboxy group as a substituent are first reacted with a reactive derivative such as anhydride including mixed anhydrides such as an acid halide such as chloride (e.g. a thionyl halide such as chloride) or a anhydride with a formic acid ester such as a (C1-C7) alkyl ester (a salt such as an ammonium or an alkali metal salt, a halogen such as a (C1-C7) alkyl ester) ) or an active ester such as cyanomethyl, nitrophenyl such as 4-nitrophenyl or polyhalophenyl such as pentachlorophenyl (a suitable hydroxy compound is a suitable condensing agent such as N, N'-dicyclohexyl). -carbodiimide).

When the compounds of formula (I) contain unsaturated groups, such as lower alkenyl groups, they can be converted into saturated groups in a manner known per se. The hydrogenation of the multiple bonds can be carried out, for example, by catalytic hydrogenation in the presence of hydrogenation catalysts, and the catalysts are, for example, nickel, for example Raney nickel, and precious metals or their derivatives, such as oxides such as palladium, platinum oxide, in condition. Hydrogenation conditions: Preferably, a pressure of from about 1 to about 100 at room temperature and from about -80 to about 200, most preferably from about room temperature to about 100. Suitable solvents for the reaction include water, a lower alkanol such as ethanol, isopropanol or n-butanol, an ether such as dioxane, or a lower alkanecarboxylic acid such as acetic acid.

Salts of the compound of formula (I) may be prepared in a manner known per se. For example, the acid addition salts of the compounds of formula (I) may be obtained by treatment with an acid or a suitable ion exchanger. The salts may be converted into the free compounds in the usual manner, for example by treatment with an acidic base, of the acid addition salts.

Depending on the process and the reaction conditions, the salt-forming, mainly basic, compounds of formula I can be obtained in free form or preferably in the form of their salts.

Due to the close association between the free form and the salt form of the novel compounds, the term "free compounds" and their salts, as used hereinbefore and hereinafter, are understood to include, where appropriate, the corresponding salts and free compounds.

The novel compounds, including salts of the salt-forming compounds, may be prepared in the form of their hydrates or other solvents used in their crystallization.

Depending on the choice of starting material and working method, the new compounds may be in the form of one of the possible isomers or of mixtures thereof, for example depending on the number of asymmetric carbon atoms, pure optical isomers such as antipodes or isomeric mixtures such as racemates, diastereoisomeric mixtures or racemates. In the corresponding compounds of formula I wherein R _{2 is,} for example, an optionally esterified carboxy group, the carbon atom of the sub-structure -X ₂ -R ₂ is preferably in the L-configuration.

The resulting racemates and diastereomeric mixtures can be separated into the pure isomers or racemates by known methods, such as fractional crystallization, based on the differences in the physicochemical properties of the ingredients. The resulting racemates can then be cleaved into optical antipodes by known methods, such as recrystallization from an optically active solvent, chromatography on a chiral adsorbent, appropriate microorganisms, cleavage with specific immobilized enzymes, formation of inclusion compounds such as chiral crown ethers, one of the enantiomers forms a complex - or by conversion to a diastereomeric salt. For example, a diastereomeric mixture obtained by reacting a basic end-product racemate with an optically active acid such as a carboxylic acid such as tartaric or malic acid or a sulfonic acid such as camphorsulfonic acid may be separated into diastereomers based on their various solubilities. Isolation of the more potent enantiomer is preferred.

Also included within the scope of the invention are embodiments of the process wherein the process is started from an intermediate obtained at any step and the missing process steps are performed or a starting material in the form of a derivative or a salt and / or racemate or antipode thereof. or mainly under reaction conditions.

The process of the present invention preferably utilizes starting materials that lead to compounds which are particularly preferred in the introduction. Particularly preferred starting materials L ~ _X the cyano group (IIa), and tautomeqei and salts of such compounds.

The invention also relates to a method of treating a compound of formula (I) or a pharmaceutically acceptable salt of such a salt-forming compound.

EN 219 343 Β ti, mainly as angiotensin II antagonists. They are preferably used in the form of pharmaceutical compositions for use in the prophylactic and / or therapeutic treatment of animal or human organisms, in particular as angiotensin II antagonists.

The invention also relates to a process for the preparation of a pharmaceutical composition containing the compounds of the invention or their pharmaceutically acceptable salts as active ingredients.

Pharmaceutical compositions containing the compounds of the present invention, or pharmaceutically acceptable salts thereof, are suitable for enteral, e.g., oral, rectal and parenteral administration to warm-blooded patients, and include the active ingredient alone or in association with pharmaceutically acceptable carriers. The daily dose will depend on the age and individual characteristics and the route of administration.

For example, the novel pharmaceutical compositions contain from about 10% to about 80%, preferably from about 20% to about 60%, by weight of the active ingredient. Pharmaceutical compositions of the invention suitable for enteral or parenteral administration may be in the form of dragees, tablets, capsules or suppositories, and in ampoules. They are prepared by methods known per se, for example, by conventional mixing, granulating, pelleting, dissolving or lyophilizing processes. For example, a pharmaceutical composition for oral administration may be prepared by admixing the active ingredient with a solid carrier, optionally granulating the mixture, and preparing the mixture or granules, if desired or necessary, in the form of tablets or dragees.

Suitable carriers are, in particular, fillers such as sugars such as lactose, sucrose, mannitol or sorbitol, cellulose formulations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and binders such as starch corn, wheat, rice or potato starch, and in addition tragacanth, methylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrating agents such as the aforementioned starches, in addition to carboxymethyl starches, (vinylpyrrolidone), agar, alginic acid or a salt thereof such as sodium alginate; excipients are in particular absorbent, flow-regulating and lubricating agents, for example silica, talc, stearic acid or a salt thereof such as magnesium or calcium stearate, and / or polyethylene glycol. The dragee cores may be coated with suitable, optionally weed-resistant coatings, which may be prepared, inter alia, by concentrated sugar solutions, optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium oxide in a suitable organic solvent or solvent mixture. in the preparation of weed-resistant coatings, solutions of suitable cellulose compositions such as acetyl cellulose phthalate or hydroxymethyl cellulose phthalate are used. For example, tablets or dragee coatings may be mixed with coloring agents or pigments to identify or recognize formulations containing different amounts of the active ingredient.

Other formulations suitable for oral administration include gelatin opening capsules and soft closed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Opening capsules contain the active ingredient in granular form, for example, in admixture with excipients such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and these solutions or suspensions may contain stabilizers similar to those of openable capsules.

Suitable formulations for rectal administration are, for example, suppositories which consist of a combination of the active ingredient and a suppository base. Examples of suppository bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. Gelatin rectal capsules containing the active ingredient and a starting material may also be used. Examples of starting materials are liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.

For parenteral administration, solutions of the water-soluble form of the active ingredient in water and suspensions of the active ingredient, for example, in the form of oily injection suspensions or suitable lipophilic solvents or agents such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides, are used. which include viscosity enhancing agents such as sodium carboxymethylcellulose, sorbitol and / or dextran and optionally stabilizers.

The dosage of the active ingredient depends on the warm-blooded species, its age, its individual characteristics and the mode of administration. Normally, for a patient weighing about 75 kg, the recommended daily dose is about 10-250 mg for oral administration.

The following examples illustrate the invention in greater detail, but are not intended to limit the invention thereto. Temperature values are given in degrees Celsius.

In the examples, the following run systems were used for the chromatography:

Neutral systems

NI ethyl acetate / hexane 2: 1

N 2: ethyl acetate / hexane 1: 1

N3 ethyl acetate / hexane 1: 2

N4 ethyl acetate / hexane 1: 4

N5 ethyl acetate / hexane 1: 9

N6 CH ₂ Cl ₂ / methanol 95: 5

N 7 CH ₂ Cl ₂ / methanol 9: 1

N8 CH ₂ Cl ₂ / MeOH 4: 1

N9 CH ₂ Cl ₂ / methanol 2: 1

N10 CH ₂ Cl ₂ / methanol 1: 1

HU 219 343 Β

Basic systems

Bl CH ₂ Cl ₂ / methanol / concentrated ammonia 40: 10: 1

B2 CH ₂ Cl ₂ / methanol / concentrated ammonia 50: 10: 1

B3 CH ₂ Cl ₂ / methanol / concentrated ammonia 60: 10: 1

B4 CH ₂ Cl ₂ / methanol / concentrated ammonia 80: 10: 1

B5 CH ₂ Cl ₂ / methanol / concentrated ammonia 100: 10: 1

B6 ethyl acetate / ethanol / concentrated ammonia 24: 12: 4

B7 toluene / isopropanol / concentrated ammonia 170: 30: 2 Acid systems

SiO ₂ CH ₂ Cl ₂ / methanol / water / acetic acid 150: 50: 10: 1

S2 toluene / isopropanol / acetic acid 170: 30: 2

Products chromatographed on basic (i.e., concentrated ammonia) run systems containing acidic functional groups are, after chromatography, taken up in an organic solvent such as diethyl ether, acetic acid or dichloromethane. The organic mixture is then washed successively with (about 1N) hydrochloric acid, water and saturated sodium chloride solution, and the organic phase is dried and evaporated. In this way, a product is obtained which contains a liberated acidic group.

Example 1

N-carboxymethyl-N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

A mixture of 1.2 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-methoxycarbonylmethyl-N-pentanoylamine, 2.18 g of tributyltin azide and 40 ml of xylene is added. reflux for an hour. The reaction mixture was then narrowed and 1N sodium hydroxide solution was added to the residue and stirred at room temperature for 10 hours. It is then extracted with diethyl ether, the aqueous phase is acidified and extracted with diethyl ether. This second ether layer was washed with brine, dried and evaporated, and the crude product was purified by flash chromatography (100 g silica gel; B1 system). to give an amorphous product having _Rf value: 0.29 (CH ₂ Cl ₂ / methanol / concentrated ammonia = 30: 10: 1).

The starting material can be prepared as follows:

a) 2 '-Cyano-4-formylbiphenyl

A mixture of 250 g of 4-bromomethyl-2'-cyanobiphenyl, 150 g of sodium acetate and 2.5 liters of glacial acetic acid was refluxed overnight. The reaction mixture was reduced under high vacuum and the residue taken up in ethyl acetate. The reaction mixture was washed successively with water, sodium bicarbonate solution and brine and concentrated in a rotary evaporator. The crude product was dissolved in 3.1 L of ethanol, treated with 430 mL of 2N sodium hydroxide solution, stirred overnight at room temperature, then filtered and the residue was taken up in ethyl acetate. The mixture was washed successively with water and sodium carbonate solution and evaporated. The residue is suspended in hexane, the suspension is filtered, the filtrate is washed and dried under high vacuum at 60 ° for 20 hours. 2'-cyano-4-hydroxymethylbiphenyl is thus obtained in the form of a white powder. 1 H-NMR (DMSO-d ₆ ): 4.58 ppm (d, 2H); 5.3 ppm (t, 1H); 7.6-8.0 ppm (m, 8H)].

A solution of oxalyl chloride (2 mL) in 2 L dichloromethane was cooled to -60 ° and at this temperature a solution of 88 mL dimethyl sulfoxide in 150 mL dichloromethane was added dropwise and the reaction mixture was stirred for 2 minutes. A solution of 117 g of 2'-cyano-4-hydroxymethylbiphenyl in 1 liter of dichloromethane is then added dropwise at -60 °. After the addition was complete (about 5 minutes), the reaction mixture was stirred for 15 minutes. Triethylamine (390 mL) was then added dropwise. The reaction mixture was stirred for 2 minutes at -60 ° C, then allowed to warm to room temperature and then poured into water. The mixture was extracted with dichloromethane and the organic layer was washed successively with hydrochloric acid and brine, dried and evaporated. The residue is suspended in hexane, the suspension is filtered, the filtrate is washed and the product is dried under high vacuum at 60 °. (Elemental analysis: 80.7% C; 4.5% H; 6.7% N; 7.7% O)

b) N- (2 '-Cyanobiphenyl-4-ylmethyl) -N-methoxycarbonylmethylamine

A mixture of 2.0 g of 2'-cyano-4-formylbiphenyl, 1.22 g of 2-aminoethanoic acid methyl ester hydrochloride, 9.6 g of molecular sieve 5A and 26 ml of tetrahydrofuran was stirred at room temperature for 36 hours, then cooled to 0 ° C to 5 ° C. A solution of sodium cyanoborohydride (680 mg, 90%) in methanol (4.8 mL) was then added. The reaction mixture was stirred for 24 hours at room temperature and then concentrated in vacuo. The crude product was purified by flash chromatography (180 g silica gel; ethyl acetate / petroleum ether = 1: 1). [?] NMR (DMSO-d6: 3.63 ppm (s, 3H); 3.79 ppm (s, 2H); 7.4-8.0 ppm (m, 10H); 2.6 ppm (1H)) .]

c) N- (2 '-Cyano-biphenyl-4-ylmethyl) -N-methoxycarbonylmethyl-N-pentanoylamine

0.96 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-methoxycarbonylmethylamine was dissolved in 9 ml of dichloromethane. Triethylamine (1.7 ml) was added followed by pentanoyl chloride (1.5 ml) at 0 ° C. The reaction mixture was stirred at room temperature overnight and then concentrated to dryness. The residue was taken up in diethyl ether and the ether mixture was washed successively with sodium bicarbonate solution and brine. Flash chromatography (180 g silica gel; acetic acid ethyl ester / petroleum ether = 1: 1 system) after the product as a white powder shafts _(Rf value: 0.68; N 2 system).

Example 2 (S) -N- (1-Carboxyethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

As in Example 1, 1.24 g of Nvaleryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -alanine methyl ester and 2.73 g of tributyltin starting from azide, after flash chromatography (B3) followed by recrystallization from ethyl acetate, the product, which is melted at 115 ° C with decomposition as a white powder.

For example, the starting material may be prepared as follows:

a) N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -alanine methyl ester from 2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 1.34 g (L). ) -alanine methyl ester hydrochloride, 680 mg of sodium8

Starting from cyanoborohydride and 2.4 g of molecular sieve 5A, it is obtained by flash chromatography on N3 system. TLC (Nj) 0.59R _r .

b) N-Valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -alanine methyl ester 1.65 g of N - [(2'-cyanobiphenyl) starting from methyl (L) -alanine methyl ester, 2.7 ml of triethylamine and 2.35 ml of n-valeric acid chloride and then flash chromatography on N2 system. TLC on N2 system shows 0.62 R _r .

Example 3 (S) -N- (1-Methoxycarbonyl-ethyl) -N-pentanoyl-N- [2- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

0.3 g of the acid prepared according to the procedure of Example 2 are dissolved in 5 ml of methanol, 0.5 ml of hydrochloric acid methanol are added and the mixture is stirred for 24 hours at room temperature. The reaction mixture was evaporated, the residue was taken up in methylene chloride, extracted with water, the organic phase was dried and concentrated on a rotary evaporator. Flash chromatography (B1) affords the product as an amorphous material; m.p. 57-59 ° C.

Example 4

N- [l-Carboxy-2- (4-fluorophenyl) ethyl] -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

2.3 g of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] (DL) -p-fluorophenylalanine methyl ester and 3.25 g of tributyltin starting from azide, after flash chromatography (B1) the product is lyophilized from tert-butyl alcohol. FAB-MS: m / e 502 (M + H) < + >.

For example, the starting material may be prepared as follows:

The N - [(2'-cyanobiphenyl-4-yl) methyl] - (DL) -p-fluorophenylalanine methyl ester from 2.33 g of 2'-cyanobiphenyl-4-carbaldehyde, Starting from 63 g of (DL) -p-fluorophenylalanine methyl ester, 790 mg of sodium cyanoborohydride and 11.0 g of a 5A Melecula filter after flash chromatography on N3. TLC on N2 system shows 0.36 R _r .

N-Valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (DL) p-fluorophenylalanine methyl ester 2.1 g of N - [(2'-cyano) -biphenyl-4-yl) methyl] - (DL) -p-fluorophenylalanine methyl ester, 1.0 ml triethylamine and 0.85 ml n-valeric acid chloride and flash chromatography (N3) done swallowing. TLC on N2 system shows 0.64 R _r .

Example 5

N- [2- (4-Fluoro-phenyl) -l-methoxycarbonyl-ethyl] -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] amine

As in Example 3, the N-valeryl-N - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl) - (DL) -p-fluoro- Starting with 1.29 g of phenylalanine FAB-MS: m / e 516 (M + H) ⁺ .

Example 6

N- [2- (4-Fluoro-phenyl) -l-hydroxymethyl-ethyl] -N-pentanoilN- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

0.5 g of N-valeryl-N - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl) - (DL) -p-fluorophenylalanine methyl mentioned in Example 5 To the ester was added 1.9 ml of diisobutylaluminum hydride in 5 ml of tetrahydrofuran at -70 ° C. After 20 minutes, 0.2 ml of methanol was added and the mixture was allowed to warm to room temperature. The product was separated, washed with brine, dried and evaporated to afford the corresponding aldehyde by flash chromatography (B2) by adding 27 mg of sodium borohydride in 5 ml of ethyl alcohol at 0 DEG C. and 3.5 hours. Stir at 0 ° C. After filtration and evaporation followed by flash chromatography (N8) and lyophilization from tert-butyl alcohol, FAB-MS: m / e 488 (M + H) ⁺ .

Example 7

N- (2 '-Carboxy-biphenyl-4-ylmethyl) -N- [1-carboxy-2- (4-fluorophenyl) -ethyl] -N-pentanoylamine

For N-valeryl-N - [(2'-carboxybiphenyl-4-yl) methyl] - (DL) p-fluorophenylalanine methyl ester in a mixture of 10 ml of methanol and 3 ml of water 0.45 2 ml of sodium hydroxide solution are added. The reaction mixture was stirred overnight at room temperature and then neutralized with 0.45 mL of 2N hydrochloric acid. Flash chromatography on B1 and lyophilization from tert-butanol gave the product as an amorphous material. FAB-MS: m / e 478 (M + H) < ⁺ & gt ^; .

Example 8

N- (2'-Carboxy-biphenyl-4-yl-methyl) -N- [2- (4-fluoro-phenyl) -1-methoxycarbonyl-ethyl] -N-pentanoylamine

840 mg of N-valeryl-N - {[2 '- (trimethylsilyl-ethoxycarbonyl) -biphenyl-4-yl] -methyl} - (DL) -p-fluorophenylalanine methyl ester in 10 ml of dimethyl- Formamide (15.6 mL, 0.5 M tetrahydrofuran, tetrabutylammonium fluoride) was added and stirred overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in ethyl acetate, washed with water and brine, dried and evaporated. After flash chromatography in B4 system and lyophilization from tert-butanol, the product is swallowed. FAB-MS: m / e 492 (M + H) < ⁺ & gt ^; .

For example, the starting material may be prepared as follows:

14.2 g of 4-methyl-2'-carboxybiphenyl (EP 253 310) are dissolved in a mixture of 60 ml of acetonitrile and 10.7 ml of pyridine and 11.4 ml of trimethylsilyl ethanol are added. At 0 ° C

Dicyclohexylcarbodiimide (15.1 g) was added to the reaction mixture and stirred at this temperature for 3 hours. It is then concentrated under high vacuum, ether is added and the dicyclohexylurea is filtered off. Flash chromatography (ethyl acetate / hexane 95: 5) gave 4-methyl-2 '- (trimethylsilyl-ethoxycarbonyl) -biphenyl as a pale yellow oil. The value of 95 would _Rf ethyl acetate / hexane-based thin-layer chromatographic examination system 5 0.42.

HU 219 343 Β

312 mg of 4-methyl-2 '- (trimethylsilylethoxycarbonyl) biphenyl, 178 mg of N-bromosuccinimide, 5 mg of azo-isobutyronitrile and 15 ml of carbon tetrachloride were refluxed for 1 hour. After cooling, the reaction mixture was evaporated. Flash chromatography (ethyl acetate / hexane 95: 5) gave 4-bromomethyl-2 '- (trimethylsilyl-ethoxycarbonyl) -biphenyl as a pale yellow oil. 1 H-NMR (CFCl ₃ ): 0 ppm (s, 9H), 0.7 ppm (t, 2H), 4.5 ppm (s, 2H), 7.1-8 ppm (aromatics).

2.8 g of 4-bromomethyl-2 '- (trimethylsilylethoxycarbonyl) biphenyl and 1.17 g of anhydrous sodium acetate in glacial acetic acid are stirred at 65 ° C overnight and then refluxed for 3 hours. while. The reaction mixture is evaporated, the residue is taken up in ethyl acetate, washed with water and sodium bicarbonate solution, the organic phase is dried and evaporated. The residue is taken up in 25 ml of ethanol, 6.3 ml of 1 N sodium hydroxide solution are added and the mixture is stirred for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo, ethyl acetate added, washed with water and brine, dried and evaporated. Flash chromatography on N4 afforded 4-hydroxymethyl-2 '- (trimethylsilyl-ethoxycarbonyl) -biphenyl as a colorless oily substance. 1 H-NMR (DMSO): 0 ppm (s, 9H), 0.75 ppm (t, 2H), 4.1 ppm (t, 2H), 4.73 ppm (d, 2H), 5.27 ppm ( t, 1H), 7.2-7.7 ppm (aromatics).

2 '- (Trimethylsilyl-ethoxycarbonyl) -biphenyl-4-carbaldehyde was reacted in a similar manner to Example 1a) to give 6.5 g of 4-hydroxymethyl-2' - (trimethylsilyl-ethoxycarbonyl) -biphenyl. 1.87 ml oxalyl chloride,

3.1 ml of dimethylsulfoxide and 13.8 ml of triethylamine. The product was eluted with methylene chloride and flash chromatographed. 1 H-NMR (CDCl ₃ ): δ ppm (s, 9H), 0.8 ppm (t, 2H), 4.2 ppm (t, 2H), 7.2-8.1 ppm (aromatics)

10.1 ppm (s, 1H).

Similar to the procedure described in Example 1b, 1.0 g of 2 '(trimethylsilylethoxycarbonyl) biphenyl-4-carbaldehyde, 4.0 g of a 5A melecula filter, 0.715 g of (DL) -p-fluorophenylalanine methyl Starting from the ester hydrochloride and 215 mg of sodium cyanoborohydride followed by flash chromatography (N3), N - {[2 '(trimethylsilyl-ethoxycarbonyl) -biphenyl-4-yl] -methyl} ( DL) -p-fluoro-phenyl-alanine methyl ester. The product has an R _r value of 0.64 in the N3 system.

Similar to the procedure described in Example 1c, 0.8 g of N - {(2 '- (trimethylsilylethoxycarbonyl) biphenyl-4-yl) methyl} (DL) -p-fluorophenylalanine methyl- Starting from the ester, 0.29 mL of triethylamine and 0.25 mL of valeryl chloride, flash chromatography (N3) affords N-valeryl {[2 '- (trimethylsilyl-ethoxycarbonyl) -biphenyl-4- yl] methyl} (DL) -fluoro-phenylalanine methyl ester. The product _Rf value based thin-layer chromatographic examination system N3 0.65.

Example 9 (S) -N- (2'-Carboxybiphenyl-4-ylmethyl) -N- (1-hydroxymethyl-2- (p-fluorophenyl) ethyl) -N-pentanoyl- amine

290 mg of N- [3- (p-fluorophenyl) -1-hydroxy-2-propyl] -N- [2 '- (trimethylsilyl-ethoxycarbonyl) -biphenyl-4-ylmethyl] -valeric acid amide 3 in dimethylformamide (20 ml) was treated with 5.82 ml of a 0.5 molar solution of tetrabutylammonium fluoride in tetrahydrofuran at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in glacial acetic acid, washed with water and brine. After flash chromatography on N7 and lyophilization, the product is obtained as a white powder. FAB-MS: m / e 446 (M + H) < + >.

For example, the starting material may be prepared as follows:

Similar to the procedure described in Example 1b, 1.5 g of 2 '- (trimethylsilylethoxycarbonyl) biphenyl-4-ylcarbaldehyde, 4.5 g of the 5A molecular sieve, 0.64 g of (DL) -3-phenyl- Starting from 2-aminopropan-1-ol and 321 mg of sodium cyanoborohydride, flash chromatography in B5 gives N - {[2 '- (trimethylsilylethoxycarbonyl) biphenyl-4] -yl] methyl} -3- (p-fluorophenyl) -2-aminopropan-1-ol. 1 H-NMR (DMSO): δ ppm (2s, 9H), 0.73 ppm (2t, 2H), 2 ppm (b, 1H), 2.73 ppm (m, 3H), 3.3 ppm (m, 2H), 3.83 ppm (s, 2H),

4.1 ppm (2t, 2H), 4.6 ppm (t, 1H), 7.15-8 ppm (8H).

Similar to the procedure described in Example 1c, N - {[2 '- (trimethylsilylethoxycarbonyl) biphenyl-4-yl] methyl} -3- (p-fluorophenyl) -2-amino- (365 mg) was obtained. starting from propan-1-ol, 0.136 mL of triethylamine, 0.112 mL of valeryl chloride, and after flash chromatography on N3, N- [3- (p-fluorophenyl) -1-hydroxy-2-propyl] - N- [2 '- (trimethylsilyl-ethoxycarbonyl) -4-ylmethyl] -valeric acid amide is obtained. FAB-MS: m / e 546 (M + H) < ⁺ & gt ^; .

Example 10 (S) -N- (2'-Carboxybiphenyl-4-ylmethyl) -N- (1-hydroxymethyl-2-imidazol-4-yl-ethyl) -N-pentanoylamine

Similar to the procedure described in Example 9, 272 mg of N- [3- (imidazol-4-yl) -1-hydroxy-2-propyl] -N - {[2 '- (trimethylsilyl-ethoxycarbonyl) -biphenyl-4-yl]. ] -methyl} -valeric acid amide, starting from 5.54 ml of a solution of tetrabutylammonium fluoride and carrying out flash chromatography (B1). FAB-MS (M + H) + = 436.

The starting material may be prepared, for example, in a manner similar to that described in Example 9:

1.5 g of 2 '- (trimethylsilyl-ethoxycarbonyl) -biphenyl-4-carbaldehyde, 0.984 g of 3- (imidazol-4-yl) -2- (S) -aminopropan-1-ol dihydrochloride 321 mg of sodium cyanoborohydride and 4.5 g of molecular sieve 5A were reacted and flash chromatographed (B5) to yield N {[2 '- (trimethylsilylethoxycarbonyl) biphenyl-4-yl]. } methyl] -3- (imidazol-4-yl) -2-amino-propan-l-ol is obtained, which shows a _Rf value of 0.36 in thin layer chromatography.

0.45 g of N - {[2 '- (trimethylsilylethoxycarbonyl) biphenyl-4-yl] methyl} -3- (imidazol-4-yl) -2- (S) -aminopropane1 ol, 0.152 ml of triethylamine and 0.132 ml of valeryl chloride and flash chromatography (methylene chloride / methanol / conc. ammonia = 120: 10: 1) to give N- [3- (imidazol-4-yl) ) -l-hydroxy-2-propyl] -N {[2 '- (N-trimethylsilyl-ethoxy) -biphenyl-4-yl] methyl} valeriánsavamidot. During processing, the pH of the aqueous phase is slightly basic. FAB-MS: m / e = 536 (M + H) < ⁺ & gt ^; .

HU 219 343 Β

Example 11 (R) -N- (1-Carboxyethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

Similarly to the procedure described in Example 1, 0.84 g of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (D) -alanine methyl ester and 731 g of the title compound were obtained. mg of tributyltin azide and flash chromatography (B1). FAB-MS: m / e = 408 (M + H) < ⁺ & gt ^; .

The starting material may be prepared, for example, in a similar manner to that described in Example 1 a):

2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.6 g of molecular sieve 5A, 1.34 g of (D) -alanine methyl ester hydrochloride and 680 mg of sodium cyanoborohydride are then reacted with the product was flash chromatographed (N3) to swallow the N - [(2'-cyanobiphenyl-4-yl) methyl] - (D) -alanine methyl ester. 1 H-NMR (DMSO): 1.21 ppm (d, 3H), 3.63 ppm (s, 3H), 3.75 ppm (dd, 1H), 4.56 ppm (d, 2H), 4.58 ppm (d, 2H), 5.31 ppm (t, 1H), 7.4-8 ppm (aromatics).

Similarly to the procedure described in Example 1c, 1.25 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (D) -alanine methyl ester, 2.1 ml of triethylamine and 8 ml of valeric acid chloride and then flash chromatography of the product (N3) such as N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] (D) -alanine methyl ester swallow, which exhibits 0.61 R _{r in} thin layer chromatography on N2 system.

Example 12 (1S), (2S) -N- (1-Carboxy-2-methyl-but-1-yl) -N-pentanoylN- [2 '- (1H-tetrazol-5-yl) -bifemyl-4 yl-methyl] amine

The product was prepared from 2.0 g of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -isoleucine methyl ester and 3.19 g of tributyltin azide followed by Flash Chromatography (B1). FAB-MS (M + H) + = 450.

The starting material may be prepared, for example, as described in Example lb):

2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.5 g of molecular sieve 5A, 1.76 g of (L) -isoleucine methyl ester hydrochloride and 680 mg of sodium cyanoborohydride. After flash chromatography (ethyl acetate / hexane = 1: 3), N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -isoleucine methyl ester is swallowed. 1 H-NMR (DMSO): 1.21 ppm (d, 3H), 3.63 ppm (s, 3H), 3.75 ppm (dd, 1H), 4.65 ppm (d, 2H), 4.58 ppm (d, 2H), 5.31 ppm (t, 1H), 7.4-8 ppm (aromatics).

As in Example 1c, 1.80 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -isoleucine methyl ester, 2.7 ml of triethylamine and 2.35 ml of n-valeric acid chloride. After flash chromatography (N4), N-valeryl-N - [(2'-cyano-biphenyl-4-yl) methyl] - (L) -isoleucine methyl ester was swallowed by TLC in N3 system. It showed _Rf value of 0.43.

Example 13 (1S), (2S) -N- (1-Methoxycarbonyl-2-methyl-but-1-yl) -Npentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl 4-ylmethyl] amine

The product can be obtained from 200 mg of N-valeryl-N - {[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] -methyl} -isoleucine after flash chromatography (B1) in a similar manner to that described in Example 3. FAB-MS: m / e = 464 (M + H) < + >.

Example 14 (S) -N- (1-Carboxy-but-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] - amine

The product can be obtained after flash chromatography (B1) from 0.30 g of Nvaleryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -norvalinomethyl ester, as in Example 1. Starting with 490 mg of tributyltin azide. FAB-MS (M + H) + = 436.

The starting material may be obtained, for example, as described in Example lb):

2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.6 g of molecular sieve 5A, 1.34 g of (L) -norvaline methyl ester hydrochloride and 680 mg of sodium cyanoborohydride, followed by flash chromatography on N3 to swallow N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -norvaline methyl ester. 1 H-NMR (DMSO): 0.83 ppm (t, 3H), 1.33 ppm (m, 2H), 1.55 ppm (m, 2H), 3.62 ppm (s, 3H), 3.1 ppm (m, 1H), 7.3-8 ppm (aromatics).

Reaction was carried out in the same manner as in Example 1c)

1.5 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -norvaline methyl ester, 2.35 ml of triethylamine and 2.15 ml of n-valeric acid chloride . Flash chromatography (ethyl acetate / hexane = 1: 3) affords N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] (L) -norvaline methyl ester, which is TLC showed 0.9 R _r .

Example 15 (S) -N- (1-Methoxycarbonyl-but-1-yl) -N-pentanoyl-N- [2'H-tetrazol-5-yl) -biphenyl-4-ylmethyl] - amine

The product may be obtained in a similar manner to that described in Example 3 by starting from 200 mg of the compound prepared in Example 14 and following the reaction by flash chromatography (B1). FAB-MS: m / e = 464 (M + H) < ⁺ & gt ^; .

Example 16 (S) -N- (1-Carboxy-2-methylprop-1-yl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl methyl / amine

The product can be prepared by 1.40 g of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valinomethyl ester and 2.25 g of tributyl- reaction with tin azide followed by flash chromatography (B1). FAB-MS (M + H) ⁺ = 436. After recrystallization from ethyl acetate, the title compound melts between 105 ° C and 115 ° C.

The starting material may be obtained, for example, in a similar manner to that described in Example lb):

0.5 g of 2'-cyanobiphenyl-4-carbaldehyde, 2.5 g of molecular sieve 5A, 0.815 g of (L) -valinomethyl ester hydrochloride and 180 mg of sodium cyanoborohydride are flash chromatographed. After (N3), N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valinomethyl ester was obtained, which showed a value of 0.5 R _r in thin layer chromatography on N3 system.

1.15 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valinomethyl ester, 0.625 ml of triethylamine and 0.56 ml of n-valeran11

Acid chloride was reacted as described in Example 1c). After flash chromatography (N3), N-valeryl N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valinomethyl ester was swallowed, which in a N2 system was 0.63 R thin layer chromatography. shows _r .

Example 17 (S) -N- (1-Carboxyethyl) -N-hexanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

The product can be obtained by 2.4 g of N-caproyl N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -alanine methyl ester and 4.05 g of tributyltin azide and flash chromatography (B1). FAB-MS: m / e = 422 (M + H) < + >.

For example, the starting material may be prepared in a similar manner to that described in Example 2:

2.0 g of N - [(2'-cyanobiphenyl) -4-ylmethyl] - (L) -alanine methyl ester, 1.23 ml of triethylamine and 1.22 ml of n-caproyl chloride are reacted with N-Caproyl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -alanine methyl ester is obtained. This compound showed a 0.5 Rf value in thin layer chromatography on an N2 system.

Example 18 (S) -N-Butanoyl-N- (1-carboxyethyl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

The product was reacted with 2.25 g of N-butyryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -alanine methyl ester and 4.11 g of tributyltinazide, followed by flash chromatography. (B1) may be prepared. FAB-MS: m / e = 394 (M + H) < + >.

The starting material can be prepared, for example, as described in Example 2:

2.0 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -alanine methyl ester, 1.23 ml of triethylamine and 0.92 ml of n-butyric acid chloride were collected. N-butyryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -alanine methyl ester is obtained, on the basis of which _Rf value of thin layer chromatogram run on N 2 was 0.5.

Example 19 (S) -N- (1-Carboxyprop-1-yl) -N-pentanoyl-N - [(2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl) -amine

0.68 g of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -2-aminobutyric acid methyl ester and 1.15 g of tributyltin azide are obtained. reaction. After recrystallization from ether, the compound melts at 102-104 ° C.

The starting material may be obtained, for example, in a similar manner to that described in Example lb):

3.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 14.5 g of molecular sieve 5A, 2.23 g of (L) -2-aminobutyric acid hydrochloride and 175 mg of sodium cyanoborohydride are reacted. followed by flash chromatography (N3). Thus, the methyl N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -2-aminobutyric acid is formed. 1 H-NMR (DMSO): 0.88 ppm (t, 3H),

1.62 ppm (m, 2H), 2.53 ppm (b, 1H), 3.15 ppm (m, 1H),

3.63 ppm (s, 3H), 3.62 ppm (d, 2H), 3.81 ppm (d, 1H).

Reaction was carried out in the same manner as in Example 1c)

0.54 g of N - [(2'-cyano-biphenyl-4-yl) methyl] - (L) -2-aminobutyric acid methyl ester, 0.33 ml of triethylamine and 0.29 ml of Nvaleric acid chloride . There was thus obtained N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -2-aminobutyric acid methyl ester having an Rj value by thin layer chromatography on N2 system. 0.52.

Example 20 (S) -N- (1-Carboxy-2-cyclohexylethyl) -N-pentanoyl- [2- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

The product can be obtained by 4.0 g of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -cyclohexylalanine methyl ester and 5.8 g of tributyltin. azide and flash chromatography (B1). FAB-MS (M + H) ⁺ = 490.

The starting material may be prepared, for example, as described in Example lb):

9.35 g of 2'-cyanobiphenyl-4-carbaldehyde, 46 g of molecular sieve 5A, 10.0 g of (L) -cyclohexylalanine methyl ester hydrochloride and 3.3 g of sodium cyanoborohydride and flash chromatography (N3). The thus obtained N - [(2'-cyanobiphenyl-4-yl) methyl] - cyclohexyl-alanine methyl ester _Rf value (L), thin-layer chromatographic examination system based N3 0.45.

Similarly to the procedure described in Example 1c, 9.0 g of N - [(2'-cyanobiphenyl) -4-ylmethyl] - (L) -cyclohexylalanine methyl ester, 4.33 g of triethylamine and 75 ml of n-valeric acid chloride. Obtained after flash chromatography (N3) of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] (L) -cyclohexyl-alanine ester methyl ester _Rf value conducted scheme N3 0.55, based on TLC.

Example 21 (S) -N- (2-Cyclohexyl-1-methoxycarbonyl-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] - amine

The product is obtained in the same manner as in Example 3 starting from 1.02 g of the compound prepared according to the procedure of Example 20. FAB-MS: m / e = 504 (M + H) < + >.

Example 22 (R) -N- (1-Carboxy-2-methylprop-1-yl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl- methyl] amine

The product is all. Similarly to the procedure described in Example 1b, 3.8 g of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (D) -valinomethyl ester and 6.17 g of tributyltone are obtained. azide and flash chromatography (N8). FAB-MS (M + H) + = 436.

The starting material may be prepared, for example, as described in Example lb):

4.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 19.3 g of molecular sieve 5A, 3.8 g of (D) -valinomethyl ester hydrochloride and 1.43 g of sodium cyanoborohydride and flash chromatography (N2). The thus obtained N - [(2'-cyanobiphenyl-4-yl) methyl] - -valinmetil ester _Rf value (D), thin-layer chromatographic examination system based N3 0.56.

Reaction was carried out in the same manner as in Example 1c)

3.2 g of N - [(2'-cyanobiphenyl) -4-ylmethyl] - (D) -valinomethyl ester, 1.82 ml of triethylamine and 1.6 ml of N-valeric acid chloride. Flash chromatography is then performed. N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (D) -valinomethyl ester is obtained. FAB-MS: m / e = 407 (M + H) < + >.

HU 219 343 Β

Example 23

N- (2-methoxyethyl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

1.65 g (4.5 mmol) of crude N - [(2'-cyanobiphenyl-4-yl) methyl] -N- (2-methoxyethyl) -valeric acid amide and 1.8 g (5.5 mmol) ) A solution of tri-n-butyltin azide in 15 ml of o-xylene was heated at reflux for 20-24 hours under a gentle stream of nitrogen. After cooling, the solution was diluted with about 30 mL of toluene, 15 mL of 1N sodium hydroxide solution was added and stirred vigorously for 2 hours. The aqueous phase was separated and the pH adjusted to acidic with 16 mL of 1 N aqueous hydrochloric acid. The excellent product was isolated by extraction with ethyl acetate. The title compound is obtained in the form of an oil which is crystallized from a small amount of ethyl acetate. Melting point 120-122 ° C.

For example, the starting material may be prepared as follows:

a) 4- [N- (2-Methoxyethyl) aminomethyl] -2'-cyanobiphenyl

To a solution of 4-bromomethyl-2'-cyanobiphenyl (5.45 g, 20 mmol) in 1,4-dioxane (40 mL) was added 2-methoxyethylamine (7.5 g, 100 mmol), followed by 8-10 h. boil under reflux. The reaction mixture was thoroughly evaporated in a water-jet vacuum and the residue was dissolved in 60 ml of 2N hydrochloric acid and extracted with 60 ml of ether. The hydrochloric acid solution was separated and the pH was made alkaline with concentrated sodium hydroxide solution. The precipitated oily material was extracted with ether, the ethereal solution was washed with water, dried over magnesium sulfate and evaporated. The title compound thus obtained as an oily substance is dissolved in a little ether and a solution of hydrogen chloride gas in methanol is added. The crystalline hydrochloride thus obtained is recrystallized from 2-propanol. The product melts at 174-176 ° C.

b) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N- (2-methoxyethyl) n-valeric acid amide

4- [N- (2-methoxyethyl) aminomethyl] -2'-cyanobiphenyl hydrochloride (3.7 g, 12.2 mmol) and triethylamine (3.1 g, 31 mmol) in 50 mL To a mixture of 1,4-dioxane, 1.5 g (15 mmol) of n-valeryl chloride was added dropwise with stirring and cooling with ice water. The suspension is stirred for 4-6 hours at room temperature. The reaction mixture was concentrated in a water-jet vacuum and partitioned between water (20 ml) and ethyl acetate (200 ml). The organic phase was successively washed with 10 ml of 2N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The title compound is swallowed as an oily substance (Rf 0.51 by TLC B7) and can be reacted further in the crude state.

Example 24

N- (2-Benzyloxy-ethyl) -N-pentanoyl-N- [2 '- (tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

6.5 g (15.2 mmol) of crude N- (2-benzyloxyethyl) -N - [(2 '-cyanobiphenyl-4-yl) methyl] -n-valeric acid amide and

6.1 g of tributyltin azide were reacted and processed as described in Example 23. The crude title compound is thus swallowed, m.p. 109-110 ° C after recrystallization from a small amount of ethyl acetate.

For example, the starting material may be prepared as follows:

a) 4- [N- (2-Benzyloxyethyl) aminomethyl] -2'-cyanobiphenyl

Similarly to the procedure described in Example 23a, the title compound from 2-benzyloxyethylamine (J. Am. Pharm. Assoc., Sci. Ed. 1952, 41, 257) was purified by flash chromatography (silica gel; toluene / methanol). = 19: 1) after swallowing as a yellowish oily substance. _Rf value of the product with B7 system according to the thin layer chromatography of 0.48.

b) N- (2-Benzyloxyethyl) -N - [(2 '-cyanobiphenyl-4-yl) methyl] -n-valeric acid amide

In Example 26 b) Analogously 4- (N- (2-benzyloxy-ethyl) aminomethyl] -2'-cyano-biphenyl bleed to afford the title compound having _Rf value with TLC system B7 0.71 and can be further reacted in the crude state.

Example 25

N- (3-methoxy-prop-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

It is swallowed similarly to the procedure described in Example 23

Crude N - [(2'-cyanobiphenyl-4-yl) methyl] -N- (3-methoxypropyl) -n-valeric acid amide (2.1 g, 5.8 mmol) and 2.3 g ( Tri-n-butyltin azide (6.9 mmol) was reacted with 20 ml of o-xylene medium and purified by flash chromatography to give the title compound as a viscous oil and Rf = 0 by TLC (B6). 33rd

For example, the starting material may be prepared as follows:

a) 4- [N- (3-Methoxy-propyl) -aminomethyl] -2'-cyano-biphenyl

As in Example 23a, the title compound is swallowed from 3-methoxypropylamine to give the hydrochloride m.p. 183-184 ° C (recrystallized from 2-propanol / ether).

b) N- [2 '-Cyano-biphenyl-4-yl) -methyl] -N- (3-methoxy-propyl) -n-valeric acid amide

The compound prepared in Example 25a was swallowed by the same procedure as in Example 23b, which had an Rp of 0.55 based on thin layer chromatography on B7 and was further reacted in the crude state.

Example 26

N- (3-Benzyloxy-prop-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

5.8 g (13 mmol) of the compound prepared in Example 26b) and 5.3 g (16 mmol) of tri-n-butyltin azide are reacted and processed as in Example 23. The crude title compound thus obtained as an oily substance was crystallized from a small amount of 2-propanol / ether. The product melts at 112-115 ° C.

For example, the starting material may be prepared as follows:

a) 4- [N- (3-Benzyloxypropyl) aminomethyl] -2'-cyanobiphenyl

6.0 g (22 mmol) of 4-bromomethyl-2'-cyanobiphenyl, 5.8 g (35 mmol) of 3-benzyloxypropylamine and 3.6 g of triethylamine

A solution of 1,4-dioxane (343 Β ml) was refluxed for 18 hours. Workup similar to that described in Example 23a afforded an oily material which was purified by Flash chromatography (ethanol / ethyl acetate = 1: 4). Value of the compound was obtained with _Rf B7 system according to the thin layer chromatography of 0.39.

b) N- (3-Benzyloxy-pronyl) -N - [(2 '-cyano-biphenyl-4-yl) methyl] -n-valeric acid amide

2.0 g (16.7 mmol) of n-valeryl chloride are added dropwise, while cooling in a water bath and 5.5 g (15.4 mmol) of the compound prepared in Example 26a) and 4.0 g of triethylamine are added dropwise. 40 ml of a solution of 1,4-dioxane. The reaction mixture is stirred for 5-10 hours at room temperature and worked up as described in Example 23a). to give the title compound as an oil _(Rf value of B7 system: 0.57). The product can be used without purification in the subsequent reaction step.

Example 27

N- (2-hydroxyethyl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

A solution of 2.6 g (5.5 mmol) of the compound prepared in Example 24 in 90 ml of 1,4-dioxane was hydrogenated at room temperature for a total of 2.0 g of palladium-on-carbon (5%) until TLC. the presence of starting material can no longer be detected (approximately 70 hours). The catalyst was then filtered off, the filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried and concentrated in vacuo. A colorless foam is obtained which has a Ή-NMR spectrum identical to that of the title compound and has an R _r value of 0.60 (based on TLC in B6).

Example 28

N- (3-Hydroxy-prop-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

2.7 g (5.5 mmol) of the compound prepared in Example 26 were hydrogenated and worked up as in Example 27. This gave a yellowish oily substance which, after flash chromatography (S2 system), afforded the title compound as a colorless foam. The product _Rf value of 0.26 (system S2).

Example 29

N- (1-Methoxycarbonyl-1-methylethyl) -N-pentanoyl-N- [2- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

9.4 g (24 mmol) of crude 2-amino-N - [(2'-cyanobiphenyl-4-yl) methyl] -2-methyl-N-valerylpropanoic acid methyl ester and 9.7 g Tri-n-butyltin azide (29 mmol) was heated under reflux for 30 hours in 120 mL of oxylol and the reaction mixture was worked up as described in Example 23. The title compound thus obtained as an oily substance was purified by flash chromatography on B6 system. The product was foam-shaped and was found to have an Rp of 0.39 based on TLC B6.

For example, the starting material may be prepared as follows:

a) 2-Amino-N - [(2 '-cyanobiphenyl-4-yl) methyl] -2-methylpropanoic acid methyl ester

10.9 g (40 mmol) of 4-bromomethyl-2'-cyanobiphenyl,

18.4 g (120 mmol) of 2-amino-2-methylpropanoic acid methyl ester hydrochloride (D. Leibfritz et al., Tetrahedron 1982, 38, 2165) and 22 g of potassium carbonate in 100 ml of dimethylformamide are stirred. Heat at 80 ° for 18-20 hours. The resulting slurry was filtered, the filtrate was concentrated in vacuo and the residue partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer was separated and washed successively with water (30-30 mL) and brine, dried and evaporated. The crude title compound is thus obtained. The product forms the hydrochloride, m.p. 170-175 ° C after recrystallization from 2-propanol.

b) 2-Amino-N - [(2 '-cyanobiphenyl-4-yl) methyl] -2-methyl-Nvalerylpropionic acid methyl ester

To a solution of 7.4 g (24 mmol) of the compound prepared as in Example 29a (base) and 3.7 g (29 mmol) of ethyl diisopropylamine in 100 mL of methylene chloride was added 3.5 g (29 mmol) of valeryl. chloride is added dropwise. The reaction mixture was stirred for 20-25 hours at room temperature until TLC indicated no starting amine (system B7). Work up as described in Example 23b) to yield the title compound as a yellowish oily substance having an R _r of 0.40 (system B7) which was used crude in the subsequent reaction.

Example 30

N- (2-carboxyethyl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

393 mg of N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl-3-aminopropanoic acid ethyl ester were reacted in the same manner as in Example 1. The crude product was purified by chromatography on silica gel 60 (40-63 µm particle size) with CH ₂ Cl ₂ / MeOH = 95: 5. _Rf value of the product is carried out N8 system according to the thin layer chromatography of 0.15.

For example, the starting material may be prepared as follows:

a) 3 - [(2 '-Cyanobiphenyl-4-yl) methylamino] propanoic acid ethyl ester

The product was prepared as in Example 1b from 4.145 g of 2'-cyano-biphenyl-4-carbaldehyde and 3.135 g of 3-amino-propanoic acid ethyl ester hydrochloride, and the crude product was obtained on silica gel 60 (40-63 µm), CH Purification by chromatography on ₂ Cl ₂ / MeOH 95: 5. _Rf = 0.21 (system N6).

b) N - [(2 '-Cyanobiphenyl-4-ylmethyl) -N-valeryl-3-aminopropanoic acid ethyl ester

This compound was swallowed in a similar manner to that described in Example 1c), starting from 1.542 g of 3 - [(2'14).

EN 219 343 using cyano-biphenyl-4-yl) -methyl-amino] -propionic acid ethyl ester. The product is _Rf = 0.66 (system N6).

Example 31

N- (2-carboxy-prop-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

785 mg of rac-N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl-3-amino-2-methylpropanoic acid methyl ester were reacted in a similar manner as in Example 1, and purified by extraction. The value of the product _Rf 0.29 (system N8).

For example, the starting material may be prepared as follows:

a) Rac-3-Amino-2-methylpropanoic acid methyl ester hydrochloride

The title compound was prepared from 10.312 g of rac-3-amino-2-methylpropanoic acid by dropwise addition of 7.3 ml of thionyl chloride in 100 ml of methanol. _Rf = 0.31 (system N6).

b) Rac-3 - [(2 '-Cyanobiphenyl-4-yl) methylamino] -2-methylpropanoic acid methyl ester

Similarly to the procedure described in Example 1b, 4.145 g of 2'-cyanobiphenyl-4-carbaldehyde and 3.072 g of rac-3-amino-2-methylpropanoic acid methyl ester hydrochloride are reacted and The product was purified by chromatography on silica gel 60 (40-63 µm particle size) in CH ₂ Cl ₂ / MeOH 97: 3. _Rf = 0.31 (system N6).

c) Rac-N - [(2'-Cyanobiphenyl-4-yl) methyl] -N-valeryl-3-amino-2-methylpropanoic acid methyl ester

Swallow as in Example 1c using 1.542 g of rac 3 - [(2'-cyanobiphenyl-4-yl) methylamino] -2-methylpropanoic acid methyl ester. The resulting product was purified by chromatography on silica gel 60 (40-63 µm particle size) in CH ₂ Cl ₂ / MeOH = 98: 2. _Rf = 0.66 (system N6).

Example 32

N- (1-Carboxy-1-methyl-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

To a solution of the ester prepared in Example 29 (2.6 g, 6 mmol) in methanol (30 ml) was added sodium hydroxide solution (35 ml) in 20% water and refluxed (about 35-40 hours). whereas, by TLC (B6 system), no starting ester is present in the reaction mixture. The solution was filtered, the methanol was evaporated in vacuo and the pH of the remaining aqueous solution was adjusted to 1-2 with concentrated hydrochloric acid. The precipitated product is extracted with 200 ml of ethyl acetate, the organic phase is separated off, washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography using a mixture of 360 ml of methylene chloride, 40 ml of methanol, 4 ml of water and 2 ml of acetic acid as eluent. The single product-only fractions were combined and evaporated. This affords the title compound as a colorless foam, _Rf value of 0.33 which showed with the above-mentioned system, thin layer chromatography assay.

Example 33

N- (5-Hydroxy-pent-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

6.5 g (17 mmol) of crude N - [(2'-cyanobiphenyl-4-yl) methyl] -N- (5-hydroxypentyl) -n-valeric acid amide and 6.8 g (20.4 mmol) ) A solution of tri-n-butyltin azide in 70 ml of o-xylene was reacted and processed in a similar manner to that described in Example 23. The crude product thus obtained was purified by flash chromatography (B6 system). From the ammonium salt of the title compound so isolated, the free tetrazole is liberated with 1N hydrochloric acid and extracted with ethyl acetate. The product is a yellowish glassy material having an R _r value of 0.20 (in B6 system) which can be crystallized from ethyl acetate; 117-118 ° C.

For example, the starting material may be prepared as follows:

a) 4- [N- (5-Hydroxypentyl) aminomethyl] -2'-cyanobiphenyl

6.8 g (25 mmol) of 4-bromomethyl-2'-cyanobiphenyl and

A solution of 5-amino-1-pentanol (12.9 g, 125 mmol) in 1,4-dioxane (50 mL) was heated at reflux for 2-3 hours. Work up as in Example 23a using ethyl acetate as solvent to swallow the title compound as its hydrochloride. After recrystallization from 2-propanol, the product melts at 189-190 ° C.

b) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N- (5-hydroxypentyl) -n-valeric acid amide

5.1 g (17.3 mmol) of the compound prepared in Example 33a) and 2.3 g (19 mmol) of n-valeryl chloride were treated with 9 ml of ethyl diisopropylamine and 50 ml of methanol to give 26 g of the title compound. The title compound was swallowed in the form of an oily substance, similar to the procedure described in Example 1B. The product having an R _r value of 0.36 (B7 system) is further reacted without purification.

Example 34

N- (l-carboxy-prop-2-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

3,390 g of rac-N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl-3-aminobutanoic acid methyl ester were reacted in the same manner as in Example 1 and purified by extraction. _Rf = 0.30 (system N8).

For example, the starting material may be prepared as follows:

a) Rac - [(2 '-Cyanobiphenyl-4-yl) methylamino] butanoic acid ethyl ester

The product was prepared in a similar manner to that described in Example 1b) from 4.145 g of 2'-cyano-biphenyl-4-carbaldehyde and 4.634 mL of ethyl 3-aminobutanoic acid ethyl ester. The resulting compound was purified by chromatography on silica gel 60 (40-63 µm particle size), eluting with CH ₂ Cl ₂ / methanol = 98: 2. Rf = 0.25 (in N6 system).

b) Rac-N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valeryl-3-aminobutanoic acid ethyl ester

Similarly to the procedure described in Example 1c, 7.070 g of rac-3 - [(2'-cyanobiphenyl-4-yl) methylamino] butanoic acid ethyl15

The title compound is obtained from the ester by purification by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH = 99: 1. _Rf = 0.36 (system N6).

Example 35

N- (2-ethoxycarbonyl-3-methylbut-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

2.194 g of ethyl ethyl rac-N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl-2- (aminomethyl) -3-methylbutanoic acid as described in Example 1. and purify by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH. _Rf = 0.48 (system N8).

For example, the starting material may be prepared as follows:

a) Rac-2 - [(2 '-Cyanobiphenyl-4-yl) methylaminomethyl] -3-methylbutanoic acid ethyl ester

As described in Example 1b, 4.145 g of 2'-cyanobiphenyl-4-carbaldehyde and 3.180 g of rac-2-aminomethyl-3-butanoic acid ethyl ester [Miyazaki et al., J. Pharm. Soc. Jpn. 77, 415 (1957)] to give the title compound which was purified by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH 97: 3. Rf = 0.48 (in N6 system).

b) Rac-N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valeryl-2-aminomethyl-3-methylbutanoic acid ethyl ester

Similarly to the procedure described in Example 1c, the title compound was obtained from 2.519 g of rac-2 - [(2'-cyanobiphenyl-4-yl) methylaminomethyl] -3-methylbutanoic acid, which was Purify by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH = 99: 1. _Rf = 0.67 (system N6).

Example 36

N- (2-Carboxy-3-methyl-but-1-yl) -N-pentanoyl-N- [2- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

980 mg rac-N - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -N-valeryl-2- (aminomethylbutanoic acid ethyl ester)

3.1 ml of 2N sodium hydroxide solution was heated at 100 ° for 72 hours. The reaction mixture was neutralized with 3.1 ml of 2N hydrochloric acid and extracted with CH ₂ Cl ₂ . The title compound is thus obtained as _Rf value of 0.30 (system N8).

Example 37 (S) -N- (1-Carboxy-2-methylprop-1-yl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl- methyl] amine

4.2 g N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] (L) -valine benzyl ester in 40 ml o-xylene 5.7 g tri-n-butyl -on-azide is refluxed for 24 hours. The reaction mixture was then evaporated to dryness. The crude product is taken up in 40 ml of dioxane, 400 mg of palladium on carbon (5%) is added and hydrogenated to saturation under normal pressure. The catalyst is filtered off, the filtrate is evaporated, the residue is taken up in ether and the product is extracted with 18 ml of 1N sodium hydroxide solution and 100 ml of water. The aqueous phase was washed with ether and, after acidification with excess 1N hydrochloric acid, extracted with ethyl acetate. After recrystallization from diisopropyl ether, the pure product melts at 116-117 ° C.

For example, the starting material may be prepared as follows:

a) N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester

4.38 g of 2'-cyano-biphenyl-4-carbaldehyde, 8.03 g of (L) valine benzyl ester toluenesulfonic acid salt and 25 g of 5 A molecular sieve are stirred in 80 ml of tetrahydrofuran for 36 hours at room temperature and then 0 °. Cool to C. A solution of sodium cyanoborohydride (2.19 g, 90%) in methanol (10 mL) was added, stirred at room temperature for 24 hours, and concentrated in vacuo. The reaction mixture was filtered, the filtrate was evaporated, the residue was taken up in methylene chloride, washed three times with water, then dried and evaporated. The residue is taken up in water and an excess of concentrated hydrochloric acid is added. An excellent product is obtained in the form of the hydrochloride. The pure material after recrystallization from ethyl acetate / hexane (1: 1) mp 153-155 ° C.

b) N-Valeryl-N - [(2 '-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester

5.5 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester hydrochloride, 4.33 g of diisopropylethylamine and 3 ml of valeryl chloride After stirring at room temperature for 36 hours, the reaction mixture was evaporated to dryness. The residue was taken up in ether and washed with sodium bicarbonate solution and brine. The crude product was further reacted without purification.

Example 38

N- (2-ethoxycarbonyl-2,2-tetramethylene-ethyl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

3.75 g of N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl1-aminomethylcyclopentane-1-carboxylic acid ethyl ester in 200 ml of o-xylene 10.4 g of tri with n-butyltin azide was refluxed for 41 hours. The reaction mixture was concentrated in vacuo, taken up in 50 ml of 2N sodium hydroxide solution and extracted three times with ether. The aqueous phase is then acidified with 30 ml of 4N hydrochloric acid and extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated. The product was swallowed in the form of a colorless foam. _Rf = 0.53 (system N8). MS (FAB): m / e 490 (M + + H).

For example, the starting material may be prepared as follows:

a) Ethyl 1-aminomethylcyclopentane-1-carboxylate g 1-cyanocyclopentane-1-carboxylate ethyl ester (Alfred Bader Chemicals) in 330 ml ethanol containing about 4% ammonia - 10 g Raney in the presence of nickel at 45 ° C under normal pressure. The catalyst was filtered off and the solvent was evaporated in vacuo. The product was distilled off by distillation. Boiling point 71-74 ° C at 0.75 mbar.

b) Ethyl N - [(2 '-Cyanobiphenyl-4-yl) methyl] -1-aminomethylcyclopentane-1-carboxylic acid

Similarly to the procedure described in Example 1 (b), 4.15 g of 2'-cyano-biphenyl-4-carbaldehyde and 4.15 g of ethyl 1-aminomethylcyclopentane-1-carboxylate are obtained.

EN 219,343 Β, which was purified by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH = 99.5: 0.5. _Rf = .38 (N6 system).

c) Ethyl N - [2 '-Cyano-biphenyl-4-yl) -methyl] -N-valeryl-1-aminomethylcyclone-1-carboxylic acid

Similarly to the procedure described in Example 1c, the title compound is obtained from 4.70 g of N - [(2'-cyanobiphenyl-4-yl) methyl] -1-aminomethylcyclopentane-1-carboxylic acid ethyl ester. which was purified by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH = 99.5: 0.5. _Rf = 0.69 (system N6).

Example 39

N- (2-carboxy-2,2-tetramethylene-ethyl) -N-pentanoyl-N- ^[(2 - (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

0.979 Ethyl N - {[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] -methyl} -N-valeryl-1-aminomethyl-cyclopentane-1-carboxylic acid was dissolved in 10 ml of ethanol. 2 ml of sodium hydroxide solution are added and the mixture is refluxed for 23 hours. The reaction mixture was cooled to room temperature and 2N hydrochloric acid (4.5 mL) was added and evaporated. The product was purified by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH 95: 5. _Rf = 0.35 (system N8). MS (FAB): m / e: 462 (M + + H).

Example 40

N- (3-Ethoxycarbonyl-cyclohexyl) -N-pentanoyl-N- [2 '(1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine and N- (3-carboxycyclohexyl) ) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

0.661 g of ethyl N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl-3-aminocyclohexane-1-carboxylic acid ethyl ester is reacted according to the procedure of Example 1 and purified by extraction. The crude product was purified by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH 95: 5. The acid has an Rp of 0.33 (N8) and an ester of 0.67 (N8). MS (FAB): m / e 462 (M + + H), 484 (M ⁺ + Na) and m / e 490 (M + + H), 512 (M ⁺ + Na).

For example, the starting material may be prepared as follows:

a) Ethyl rac-3 - [(2 '-Cyanobiphenyl-4-yl) methylamino] -cyclohexyl-1-carboxylic acid

From 2.711 g of 4-bromomethyl-2'-cyano-biphenyl and 2.055 g of ethyl 3-aminocyclohexane-1-carboxylate in the presence of N-methylmorpholine, the title compound is obtained after heating at 160 [deg.] C. for 10 minutes. compound. The crude product was purified by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH = 9: 1. _Rf = 0.73 (system N8).

b) Ethyl rac-N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valeryl-3-aminocyclohexane-1-carboxylic acid

Similarly to the procedure described in Example 1c, 0.766 g of the ethyl ester of rac-3 - [(2'-cyano-biphenyl-4-yl) -methyl-amino] -cyclohexane-1-carboxylic acid is obtained, which is isolated on silica gel 60 ( 40-63 µm). The eluent was CH ₂ Cl ₂ / MeOH = 99.5: 0.5. _Rf = 0.56 (system N6).

Example 41 Cis-N- (4-Carboxycyclohexyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

2,700 g of cis-N - [(2'-cyanobiphenyl-4-yl) methyl] -Nvaleryl-4-aminocyclohexane-1-carboxylic acid ethyl ester were reacted according to the procedure of Example 1 and purified by extraction. _Rf = 0.40 (system N8). MS (FAB): m / e 462 (M + + H).

For example, the starting material may be prepared as follows:

a) Ethyl cis-4 - [(2 '-Cyanobiphenyl-4-yl) methylamino] -cyclohexyl-1-carboxylic acid

Similarly to the procedure described in Example 1b, 4.145 g of 2'-cyano-4-carbaldehyde and 5.137 g of 4-aminocyclohexane-1-carboxylic acid ethyl ester are swallowed with silica gel 60 (40-63 µm particle size). purify by chromatography. The eluent was CH ₂ Cl ₂ / MeOH = 99.5: 0.5. Rf = 0.18 (N6 system).

b) Ethyl cis-N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valeryl-4-aminocyclohexane-1-carboxylic acid

Similar to the procedure described in Example 1c, 2.540 g of ethyl cis-4 - [(2'-cyano-biphenyl-4-yl) methylamino] -cyclohexane-1-carboxylate were swallowed with silica gel 60 (silica gel 60). 40-63 µm). The eluent was CH ₂ Cl ₂ / MeOH = 98: 2. _Rf = 0.32 (system N6).

Example 42 Cis-N- (2-Ethoxycarbonyl-cyclohexyl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

Ethyl ester of rac-cis-N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl-2-aminocyclohexane-1-carboxylic acid (1,350 g) was reacted in the same manner as in Example 1. The crude product was purified by chromatography on silica gel 60 (40-63 µm particle size). The eluent was 95: 5 CH ₂ Cl ₂ / MeOH. R _f 0.53 (N8 system). MS (FAB): m / e 490 (M + + H).

For example, the starting material may be prepared as follows:

a) Ethyl rac-cis-2 - [(2 '-Cyanobiphenyl-4-yl) methylamino] -cyclohexyl-1-carboxylic acid

Similarly to the procedure described in Example 1b, 4.145 g of 2'-cyano-biphenyl-4-carbaldehyde and 5.137 g of rac-cis-2-aminocyclohexane-1-carboxylic acid ethyl ester are obtained on silica gel 60 (40- 63 µm). The eluent was CH ₂ Cl ₂ / MeOH 99: 1. R _f 0.24 (in N6 system).

b) Ethyl rac-cis-N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valeryl 2-aminocyclohexane-1-carboxylic acid

Similarly to the procedure described in Example 1c, the title compound was swallowed from 2.110 g of rac cis-2 - [(2'-cyano-biphenyl-4-yl) methylamino] -cyclohexane-1-carboxylic acid. Silica gel 60 (40-63 µm eye17)

Purification by chromatography (CH ₂ Cl ₂ / MeOH 98: 2). R _f 0.35 (N6 system).

Example 43 Cis-N- (2-Carboxycyclohexyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

649 mg of rac cis-N - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -N-valeryl-2-aminocyclohexane-1-carboxylic acid ethyl ester in 10 ml ethanol and 2 ml of 2N sodium hydroxide solution was heated at 80 ° C for 18 hours. The reaction mixture was neutralized with 2 ml of 2N hydrochloric acid and concentrated. The crude product was purified by chromatography on silica gel 60 (40-63 µm particle size), eluting with 95: 5 CH ₂ Cl ₂ / MeOH. R _f 0.30 (N8 system). MS (FAB): m / e 462 (M + + H), 484 (M ⁺ + Na).

Example 44

N- (2-ethoxycarbonyl-2-ethyl-but-l-yl) -N-pentanoyl [2 '(lH-tetrazol-5-yl) biphenyl-4-ylmethyl-amine

3.28 g of N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl-2-aminomethyl-2-ethylbutyric acid ethyl ester are reacted as described in Example 1 and purified by extraction. . R _f 0.52 (N8 system). MS (FAB): m / e 492 (M ⁺ + H), 514 (M ⁺ + Na).

For example, the starting material may be prepared as follows:

a) 2-Aminomethyl-2-ethyl-butyric acid ethyl ester

The title compound was 12.83 g of ethyl 2-ethyl-2-cyanobutyric acid (Pfalz & Bauer Inc.) in 130 ml of ethanol containing 4% ammonia in the presence of 4 g of Raney nickel at 44 ° C and standard by hydrogenation under pressure. After removal of the catalyst, the filtrate was concentrated in vacuo and the resulting liquid was distilled in vacuo. The product boils at 0.70 mbar at 60-61 ° C.

b) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -2-aminomethyl-2-ethyl-butyric acid ethyl ester

The title compound was prepared from 2.711 g of 4-bromomethyl-2'-cyanobiphenyl and 4.332 g of 2-aminomethyl-2-ethylbutyric acid ethyl ester in a similar manner to Example 41a. The residue was purified by chromatography on silica gel (40-63 µm particle size) eluting with CH ₂ Cl ₂ / MeOH 97: 3. R _f 0.54 (in N6 system).

c) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valeryl-2-aminomethyl-2-ethylbutyric acid ethyl ester

The title compound was obtained as in Example 1c from N - [(2'-cyanobiphenyl-4-yl) methyl] -2-aminomethyl-2-ethyl-butyric acid ethyl ester. The product was purified by chromatography on silica gel 60 (40-63 µm particle size) eluting with 99: 1 CH ₂ Cl ₂ / MeOH. R _f 0.67 (in N6 system).

Example 45

N- (2-ethoxycarbonyl-2-methylprop-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

4.21 g of N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valeryl-3-amino-2,2-dimethylpropionic acid ethyl ester are reacted with

Similar to the procedure described in Example 1. The crude product was purified by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH 9: 1. R _f 0.60 (N8 system). MS (FAB): m / e 464 (M + + H), 486 (M ⁺ + Na).

For example, the starting material may be prepared as follows:

a) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -3-amino-2,2-dimethylpropionic acid ethyl ester

2.711 g of 4-bromomethyl-2'-cyano-biphenyl and 3.630 g

The ethyl ester of 3-amino-2,2-dimethylpropionic acid was obtained in a similar manner to Example 41a, which was reacted without purification. R _f 0.54 (in N6 system).

b) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valeryl-3-amino-2,2-dimethylpropionic acid ethyl ester

In a similar manner to that described in Example 1c, the title compound is obtained from 3.36 g of ethyl N - [(2'-cyanobiphenyl-4-yl) methyl] -3-amino-2,2-dimethylpropionic acid. The product is purified by extraction. R _f 0.63 (in N6 system).

Example 46

N- {2- [2- (4-hydroxyphenyl) carbonyl-ethylamino] -2,2-tetramethylene-eth} -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl ) -biphenyl-4-ylmethyl] -amine

0.507 g of N - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] N-valeryl-1-aminomethylcyclopentane-1-carboxylic acid are dissolved in 4 ml of dimethylformamide, and 0.210 g of tyramine hydrochloride, 0.225 ml of Hünig's base and 0.164 g of HOBT. The reaction mixture was cooled to 0 ° C and 0.274 g of EDCl was added. After stirring for 48 hours at room temperature, the mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and washed with 25 ml of 1N hydrochloric acid. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product thus obtained was purified by chromatography on silica gel 60 (40-63 µm particle size), eluting with 95: 5 CH ₂ Cl ₂ / MeOH. Rf 0.43 (N8 system). MS (FAB): m / e 581 (M + + H), 603 (M + + Na).

Example 47 (S) -N- {1- [2- (4-Hydroxy-phenyl) -ethylaminocarbonyl] -2-methyl-prop-1-yl} -N-pentanoyl-N- [2 '- ( tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

0.5 g of the compound prepared in Example 16, 0.21 g of tyramine hydrochloride, 0.225 ml of N-ethyldiisopropylamine, 0.164 g of 1-hydroxybenzotriazole and 0.296 g of dicyclohexylcarbodiimide are stirred at room temperature for 4 hours in 4 ml. dimethylformamide. The solvent was evaporated in vacuo and the residue was stirred with CH ₂ Cl ₂ / MeOH / AcOH 94: 3: 3 (4 mL) for 1 h. The reaction mixture was evaporated and separated by flash chromatography (100 g, N6 system). After lyophilization from tert-butanol, the product is swallowed as an amorphous powder. FAB-MS: m / e 555 (M + H) < + >.

Example 48 (S) -N- (1-Carboxy-2,2-dimethylprop-1-yl) -N-pentanoylN- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl methyl] amine

HU 219 343 Β

Obtained after flash chromatography (B2) starting from 240 mg of N-valeroyl-N - [(2'-cyanobiphenyl-4-yl) methyl] (L) -tert-leucine methyl ester and 399 mg of tributyltinazide. the title compound. The product melts at 122-124 ° C.

For example, the starting material may be prepared as follows:

a) N - [(2 '-Cyanobiphenyl-4-carbaldehyde-4-yl) methyl] - (L) tert-leucine methyl ester

2.5 g of 2'-cyanobiphenyl-4-carbaldehyde, 4.39 g of (L) t-leucine methyl ester hydrochloride, 895 mg of sodium cyanoborohydride (85%) and 1.25 g of 5A. Reaction with a molecular sieve followed by flash chromatography (N3) to yield the title compound. The product has an Rp value (based on N2 thin layer chromatography) of 0.58.

b) N-Valeryl-N - [(2 '-cyanobiphenyl-4-yl) methyl] - (L) -tercleucine ethyl ester

1.2 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -tert-leucine methyl ester are reacted with 0.65 ml of triethylamine and 0.565 ml of Nvaleric acid chloride, followed by Flash Chromatography (N4) gave the title compound. TLC on N3 system shows 0.56 R _r .

Example 49 (S) -N- (1-Methoxycarbonyl-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4 yl-methyl] amine

0.8 g of N-valeroyl-N - {[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] methyl} - (L) -valinomethyl ester was obtained in a similar manner to Example 3. Starting from 4 g of N-valeryl-N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} - (L) -valine, which is esterified in MeOH / HCl. Flash chromatography was carried out with ethyl acetate / hexane 1: 3. FAB-MS: m / e 450 (M + H) +.

Example 50 (S) -N- (1-Hydroxymethyl-2-methylprop-1-yl) -N-pentanoylN- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl methyl] amine

0.8 g of N-valeryl-N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} - (L) -valinomethyl ester is dissolved in 30 ml of tetrahydrofuran at 5 ° C. lithium borohydride (83 mg) was added and stirred at room temperature for 24 hours. The reaction mixture was evaporated, water was added and the pH was adjusted to 2 with hydrochloric acid to give a white precipitate. This was extracted with ethyl acetate, washed with water and brine, and finally separated by flash chromatography (CH ₂ Cl ₂ / MeOH 5: 1). FAB-MS: m / e 422 (M + H) < ⁺ & gt ^; .

Example 51

N- (4-Phenoxy-but-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

3.3 g (7.5 mmol) of crude N - [(2'-cyanobiphenyl-4-yl) methyl] -N- (4-phenoxybutyl) -n-valeric acid amide and 3.0 g (9 mmol) of tri N-butyltin azide is reacted and processed in a similar manner to that described in Example 23. After purification by flash chromatography (toluene / methanol 4: 1), the title compound is obtained as a viscous oil. R _f 0.50 (system B6).

For example, the starting material may be prepared as follows:

a) 4- [N- (4-Phenoxy-butyl) -aminomethyl] -2'-cyano-biphenyl

Similarly to the procedure described in Example 23a, the title compound is obtained from 4-phenoxybutylamine, the hydrochloride of which is recrystallized from isopropanol / ethyl acetate at 103-104 ° C.

b) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N- (4-phenoxybutyl) n-valeric acid amide

Compound obtained analogously as described in Example a) .b Example 23) According to give the title product as a yellow oil, which is further reacted without _Rf 0.71 (system B7), and by purification.

Example 52

N- (2-Hydroxy-l-phenyl-2-oxoethyl) -N-pentanoyl-N- [2'- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

Similarly to the procedure described in Example 1, N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valerylphenylglycine benzyl ester (11.0 g, 21 mmol) was 8.5 g (25%). 5 mmol) of tri-n-butylone azide in 6 ml of o-xylene and then hydrolyzed with 100 ml of 2N potassium hydroxide solution for 3 hours. The aqueous layer was acidified with 2N hydrochloric acid and then extracted with toluene to give the crude title compound which was crystallized from a small amount of toluene. The crystalline material has a melting point of 145-148 ° C and contains 1/3 molar equivalent of toluene.

For example, the starting material may be prepared as follows:

a) Rac-N - [(2'-Cyanobiphenyl-4-yl) methyl] phenylglycine benzyl ester

Rac-phenylglycine-benzyl ester tosylate (24.8 g, 60 mmol) and 4-bromomethyl-2'-cyanobiphenyl (8.2 g, 30 mmol) in diisopropylethylamine (15.5 g) (Hunig's base) together in 60 ml of dimethylformamide for 2 hours at 80 ° C. The reaction mixture was then poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was separated and stirred with 2N hydrochloric acid. The hydrochloride of the title compound as an oily substance was isolated, basified with sodium carbonate solution and further reacted without purification. R _f 0.65 (B7 system).

b) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valerylphenylglycine benzyl ester

9.4 g (21.7 mmol) of the crude compound prepared in Example a) are dissolved in 5.7 g (44 mmol) of Hygg base in 45 mL of methylene chloride and 3.14 g (26 mmol) of valeric acid are added. chloride is added. The solution was allowed to stand for 30-40 hours. Work up as in Example 1c) yields the crude title compound as a viscous oil. The product was reacted further without purification. _Rf 0.73 (system B7).

Example 53 (S) -N- (1-Carboxy-2-methylprop-1-yl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl- methyl] amine

21.1 g (40 mmol) of N - {[2 '- (1H-tetrazol-5-yl) biphenyl4-yl] methyl} -N-valeryl (L) -valine benzyl ester in 210 mL

Hydrogenated in methanol at room temperature (24 h) until 4 g of Pd / C (10%) was added to the calculated amount of hydrogen. The solution was filtered and concentrated to give the crude acid. This was partitioned between 80 ml of 2N potassium hydroxide solution and 50 ml of ether. The aqueous phase was separated, the pH was acidified and the title compound was extracted with ethyl acetate. The product is obtained as a crystalline material from ethyl acetate, m.p. 110-115 ° C. [alpha] -69.95 ° ± 0.05 ° (c in 1% methanol).

For example, the starting material may be prepared as follows:

a) N - [(2 '-Cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester

13.6 g (50 mmol) of 4-bromomethyl-2'-cyanobiphenyl,

22.8 g (60 mmol) of (L) -ValOBz tosylate and 34 ml of Higig base in 100 ml of dimethylformamide are stirred for 1 hour at 80 ° C. The reaction mixture was cooled, poured into ice water (300 ml) and extracted with water (150 ml). The extract was washed with water, potassium bicarbonate solution, dried and evaporated to give the crude title compound as an oily substance. The product forms the hydrochloride, m.p. 172-173 ° C.

b) N - [(2 '-Cyanobiphenyl-4-yl) methyl] -N-valeryl- (L) -valithiobenzyl ester

6.2 g (15.5 mmol) of N - [(2'-cyanobiphenyl-4-yl) methyl] (L) -valinobenzyl ester and 8.0 ml of Hünig's base with 50 ml of methylene chloride solution while stirring

Valeric acid chloride (2.3 ml) was added and the reaction mixture was worked up as described in Example 29b). The title compound is obtained in the form of a yellowish oily substance and is reacted without purification. R _f 0.51 (19: 1 toluene / methanol).

c) (S) -N- (1-Benzyloxycarbonyl-2-methyl-prop-1-yl) -Npentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4- ylmethyl] amine

6.6 g (13.6 mmol) of crude N - [(2'-cyanobiphenyl-4-ylmethyl) -N-valeryl- (L) -valine benzyl ester and 6.0 g (18 mmol) of tributyltin The azide was heated in 75 ml of o-xylene for 48 hours with stirring and refluxing, and after 24 hours, an additional 2.0 g of tributyltin azide were added to the reaction mixture, which was treated with 110 ml of 1 N potassium hydroxide solution in the same manner as in Example 23. after 20 min, was processed using the compound obtained in the form of the title compound as a yellowish oil, _Rf 0.40 (system S2) [alpha] ^ -... 36.6 ° (c 1, methanol).

Example 54 (S) -N- (1-Benzyloxycarbonyl-2-methylprop-1-yl) -Npentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4 -ylmethyl] amine g (about 100 mmol) crude N - {[2 '- (1-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl] -methyl} -N-valeryl (L) To a solution of the valine benzyl ester in 300 ml of dioxane at 60 ° C was added 300 ml of 1N hydrochloric acid and kept at 60 ° C for 2 hours. The dioxane is then evaporated in vacuo and the aqueous phase is made alkaline with 2N potassium hydroxide solution. The neutral constituents are extracted with ether. The aqueous phase was acidified and then extracted with ethyl acetate. This gives the crude title compound as an oily substance. R _f 0.40 (S2 system).

For example, the starting material may be prepared as follows:

a) N - {[2 '- (1-Triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl] -methyl} - (L) -valine benzyl ester

In a similar manner to that described in Example 56, the title compound is obtained from 4-bromomethyl-2 '- (1-triphenylmethyl-tetrazol-5-yl) -biphenyl, which is reacted further without purification. R _f 0.78 (in B6 system).

b) N - {[2 '- (1-Triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl] methyl} -N-valeryl (L) -valine benzyl ester

A compound prepared as described in a)

Reaction with 2.5 molar equivalents of valeric acid chloride and 5 molar equivalents of Hünig's base in methylene chloride is carried out in a manner similar to that described in Example 29b). The title compound was obtained without further purification.

Example 55

N-Butanoyl-N- (1-carboxy-1-methyl-ethyl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine

2-Amino-n-butyryl-2-methyl-N - {[2 '(1H-tetrazol-5-yl) -biphenyl-4-yl] -methyl} -propionic acid (2.1 g, 4.2 mmol) A solution of benzyl ester in methanol (20 ml) was hydrogenated with 0.2 g of Pd / C (10%) at an initial pressure of 5 bar until the starting benzyl ester was no longer detectable by thin layer chromatography (B6, S2 system). . The reaction mixture was filtered, the solvent was evaporated and the residue was recrystallized from CH ₃ CN. The title compound is obtained, m.p. 187-189 ° C.

For example, the starting material may be prepared as follows:

a) Benzyl 2-amino-N- (2 '-cyano-biphenyl-4-ylmethyl) -2-propionic acid

Similarly to the procedure described in Example 29a), the title compound was obtained by recrystallization from 2-amino-2-methylpropanoic acid benzyl ester tosylate in ethyl acetate and 4N hydrochloric acid in anhydrous ethanol at 200-202 ° C. are good.

b) Benzyl 2-amino-N-butyryl-N- (2 '-cyanobiphenyl-4-ylmethyl) -2-methylpropanoic acid

To a solution of 6.3 g (15 mmol) of the hydrochloride prepared in (a) and 10.2 mL (860 mmol) of hygine base in 60 mL of methylene chloride are added 1.8 g (16 mmol) of butyric acid chloride and stirring overnight. Additional acid chloride and Hünig's base were added to complete the reaction. Work up as described in Example 23b). The title compound was obtained without further purification.

c) 2-Amino-N-butyryl-2-methyl-N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} propanoic acid benzyl ester

From the compound prepared in (b) (6 g, crude product) and 5.2 g of tributyltin azide in 50 ml of oxylol, the title compound is obtained, which is recrystallized from ethyl acetate at 203-204 ° C. are.

HU 219 343 Β

Example 56

N- (4-Hydroxy-but-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

As in Example 33, the title compound was swallowed from N - [(2'-cyanobiphenyl-4-yl) methyl] -N- (4-hydroxybutyl) -n-valeric acid amide, which was recrystallized from ethyl acetate. -111 ° C.

For example, the starting material may be prepared as follows:

a) 4- [N- (4-Hydroxybutyl) aminomethyl] -2'-cyanobiphenyl

As in Example 33a, 4-aminobutanol is swallowed from the oily substance in the form of an oily substance which is reacted further without purification. _Rf 0.18 (system B7).

b) N - [(2'-Cyanobiphenyl-4-yl) methyl] -N- (4-hydroxybutyl) n-valeric acid amide

As in Example 33b, the title compound is swallowed from the compound prepared in a) in the form of an oil, which is reacted further without purification. R _f 0.37.

Example 57 (S) -N- (1-Benzyloxycarbonyl-2-methyl-prop-1-yl) -N- [3-bromo-2 '- (1H-tetrazol-5-yl) -biphenyl-4 yl-methyl] -N-amine petanoil

4.5 g (8 mmol) of N - [(3-bromo-2'-cyanobiphenyl-4-yl) methyl] -N-valeryl- (L) -valine benzyl ester and 3.4 g (4 mmol) tributyltin azide in 50 ml o-xylene was refluxed for 20 hours. The reaction mixture was worked up as described in Example 54 and purified by flash chromatography (toluene / methanol 4: 1). The title compound is thus swallowed as a colorless foam. R _f 0.57 (in S2 system).

For example, the starting material may be prepared as follows:

a) 3 '-Bromo-4' -methyl-1,1 '-biphenyl-2-carbonitrile

To a suspension of anhydrous aluminum chloride (21.0 g, 0.157 mol) in tetrachloroethane (800 ml) was added 4'-methyl-1,1'-biphenyl-2-carbonitrile (25.0 g, 0.129 mol) and stirred at 60 ° C. is heated to a temperature. As the aluminum chloride dissolved at a temperature of 60 ° C, a solution of 20.7 g (0.129 mol) of bromine in 100 ml of tetrachloroethane was added dropwise. The reaction mixture was stirred at 60 ° C for 24 hours. After addition of 6.2 g of aluminum chloride, the mixture was heated at 60-70 ° C until TLC (in toluene) showed no starting material. The reaction mixture was quenched with ice-water (20 mL) and the organic layer was separated and concentrated in vacuo. The dark residue was dissolved in ethyl acetate, washed with water and sodium carbonate solution, dried over magnesium sulfate and evaporated. The crude product was purified by flash chromatography to afford 22.0 g (62% of theory) of the title compound, m.p. 104-106 ° C after recrystallization from cyclohexane.

b) 3 '-Bromo-4' -bromomethyl-1,1'-biphenyl-2-carbonitrile

A solution of 3'-bromo-4'-methyl-1,1'-biphenyl-2-carbonitrile (8.9 g, 0.033 mol) in 900 ml of tetrachloroethane

After the addition of 0.1 g of benzoyl peroxide, a solution of bromine (5.6 g, 0.035 mol) in 20 ml of tetrachloroethane was added dropwise under UV irradiation at 100-110 ° C. After 30 minutes, the reaction mixture was cooled and concentrated in vacuo. The crystalline residue is recrystallized from ethyl acetate. 4.1 g of the title compound are obtained, m.p. 152-153 ° C.

c) N - [(3-Bromo-2 '-cyano-biphenyl-4-yl) -methyl] - (L) -valinobenzyl ester

To a solution of 4.63 g (12.2 mmol) of (L) -valine benzyl ester tosylate and 4.8 mL of Hünig's base in 20 mL of dimethylformamide are described in 3.3 g (9.4 mmol). A solution of the compound prepared according to the method of Example 1 is added and stirred for 4 hours at 100 ° C. The reaction mixture was worked up in a similar manner to Example 54a and then purified by flash chromatography (n-hexane / ethyl acetate 4: 1) to afford the title compound as a reddish brown oil. R _f 0.21 (n-hexane / ethyl acetate 4: 1).

d) N - [(3-Bromo-2 '-cyano-biphenyl-4-yl) methyl] -N-valeryl (L) -valine benzyl ester

The title compound is obtained in the form of a yellowish oily substance from the compound (c) in a similar manner to that described in Example 54b. R _f 0.17 (n-hexane / ethyl acetate).

Example 58 (S) -N- [3-Bromo-2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -N- (1-carboxy-2-methyl-prop-1-yl) ] -N-pentanoyl-amine

2.4 g (4 mmol) of N - {[3-bromo-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -N-valeryl (L) -valine benzyl- A solution of the ester in 90 ml of dioxane was hydrogenated with 1.2 g of Pd / C (10%) at 5 bar and room temperature until the calculated amount of hydrogen was taken up. The reaction mixture was filtered and evaporated, the residue was dissolved in 2N sodium hydroxide solution, extracted with ether and the pH of the aqueous phase was acidified with 2N hydrochloric acid. It was then extracted with ethyl acetate, and the extract was dried and evaporated. The title compound is swallowed as a colorless foam. R _f 0.40 (S2 system). FAB-MS: m / e 514 (M + H) < + >.

Example 59

N- (2-Acetylamino-ethyl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

9.9 g (22 mmol) of crude N- (2-acetylaminoethyl) -N- [2'-cyanobiphenyl-4-yl) methyl] -n-valeric acid amide and 12.3 g (37 mmol) Tributyltin azide was heated under reflux for 30 hours in 100 ml xylene. After cooling, the precipitate was collected by decantation and dissolved in a mixture of 100 ml of ether and 100 ml of 1 N potassium hydroxide solution (3-4 hours). The title compound was isolated from the aqueous alkaline phase by acidification with 2N hydrochloric acid and a large amount of ethyl acetate, which was then purified by flash chromatography (S2 system). The product was obtained as a solid. 74-80 ° C.

For example, the starting material may be prepared as follows:

a) N - [(2,2 '-Cyanobiphenyl-4-yl) methylaminoethyl] acetamide

HU 219 343 Β

From 9.2 g (90 mmol) of 2-aminoethylacetamide and 8.1 g (30 mmol) of 4-bromomethyl-2'-cyano-biphenyl in 100 mL of dioxane, the title compound was swallowed as described in Example 23a). which is an oily substance and is reacted further without purification.

b) N- (2-Acetylaminoethyl) -N - [(2 '-cyanobiphenyl-4-yl) methyl] -n-valeric acid amide

To a solution of 4.2 g (8.8 mmol) of the compound prepared in (a) and 5.0 mL of Hünig's base in 40 mL of methylene chloride is added 2.4 g (20 mmol) of valeric acid chloride and refluxed for 24 hours. Work up according to the procedure described in Example 23b) and purify the resulting product by flash chromatography (n-hexane / ethyl acetate 4: 1). The title compound was obtained as a yellowish oily substance. R _f 0.17 (n-hexane / ethyl acetate 4: 1).

Example 60

N- [2- (n-butoxycarbonyl) -2,2-tetramethylene-ethyl] -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] amine

0.490 g of N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -N-valeryl-1-aminomethylcyclopentane-1-carboxylic acid is dissolved in 20 ml of butanol, molecular sieve and 0.5 ml of 4N hydrochloric acid were added and refluxed for 48 hours. The reaction mixture was concentrated and purified by chromatography on silica gel 60 (40-63 µm particle size), eluting with 95: 5 CH ₂ Cl ₂ / MeOH. R _f 0.73 (in N8 system). MS (FAB): m / e 518 (M + + H), 540 (M + + Na).

Example 61

N- (2-ethoxycarbonyl-2,2-pentamethylene-hydroxyethyl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

8.70 g of N - [(2'-cyanobiphenyl-4-yl) methyl] -N-valerylaminomethylcyclohexane-1-carboxylic acid ethyl ester were reacted in a similar manner as in Example 1. The crude product was purified by chromatography on silica gel 60 (40-63 µm particle size), eluting with 95: 5 CH ₂ Cl ₂ / MeOH. R _f 0.66 (for N8 system). MS (FAB): m / e 504 (M + + H), 525 (M + + Na), 542 (M + + K).

For example, the starting material may be prepared as follows:

a) 1-Aminomethyl-cyclohexane-1-carboxylic acid ethyl ester

72.08 g of ethyl 1-cyanocyclohexane-1-carboxylate (T. Kurihara et al., Vol. Lett. 1976, 2455) in 600 ml of ethanol containing about 4% ammonia in the presence of 20 g of Raney nickel, hydrogenation at normal pressure and 45 ° C. The catalyst was removed and the solvent was evaporated to yield the title compound by distillation. The product boils under a pressure of 0.3 mbar at 72-75 ° C.

b) Ethyl N - [(2 '-Cyanobiphenyl-4-yl) methyl] -1-aminomethylcyclohexane-1-carboxylic acid

Similar to the procedure described in Example 4O.a., 5,422 g

The title compound was obtained from 4-bromomethyl-2'-cyano-biphenyl and 9.264 g of ethyl 1-aminomethyl-cyclohexane-1-carboxylic acid, which was purified by chromatography on silica gel 60 (40-63 µm), eluting with CH. ₂ Cl ₂ / MeOH 97.5: 2.5. R _f 0,67 (for N6 system),

c) N - [(2'-Cyanobiphenyl-4-yl) methyl] -N-valeryl-1-aminomethyl-1-carboxylic acid ethyl ester

Similarly to the procedure described in Example 1c, the title compound is obtained from 7.12 g of N - [(2'-cyanobiphenyl-4-yl) methyl] -1-aminocyclohexane-1-carboxylic acid, which is purified by extraction. . _Rf 0.68 (system N6).

Example 62

N- (2-benzyl-aminocarbonyl-2,2-tetramethylene-ethyl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

0.507 g of N - {[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] methyl} -N-valeryl-1-aminomethyl-cyclopentane-1-carboxylic acid as described in Example 47. 0.241 g of benzylamine and purification of the crude product by chromatography on silica gel 60 (40-63 µm particle size), eluting with 95: 5 CH ₂ Cl ₂ / MeOH. R _f 0.49 (in N8 system). MS (FAB): m / e 551 (M + + H), 573 (M ⁺ + Na).

Example 63

N- (2-Carboxy-2-ethyl-but-l-yl) -N-pentanoyl-N- [2 '- (tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

1.146 g of ethyl N - {[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] methyl} -N-valeryl-2-aminomethyl-2-ethyl-butyric acid are dissolved in 10 ml. of ethanol, 4.66 ml of 2N sodium hydroxide solution are added and the mixture is refluxed for 20 hours. The reaction mixture was cooled to room temperature, 4.66 mL of 2N hydrochloric acid was added and evaporated. The product obtained is isolated by chromatography on silica gel 60 (40-63 µm particle size). The eluent was CH ₂ Cl ₂ / MeOH 80:20. R _f 0.38 (N8 system). MS (FAB): m / e 486 (M ⁺ + Na), 502 (M ⁺ + K).

Example 64 (S) -N- (1-Carboxy-2-methylprop-1-yl) -N-ethoxycarbonylN- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl methyl] amine

0.34 g of N-ethoxycarbonyl-N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} - (L) -valine benzyl ester 0.17 g of Pd Hydrogenated in 10 ml of tetrahydrofuran under normal pressure in the presence of a catalyst (10) to saturation. The catalyst was filtered off and the crude product was purified by flash chromatography (25 g silica gel, B1 system). The title compound is obtained as an amorphous material. FAB-MS: m / e 424 (M + H +).

For example, the starting material may be obtained as follows:

a) N- (Ethoxycarbonyl) -N - [(2 '-cyanobiphenyl-4-yl) methyl] (L) -valine benzyl ester

10.0 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valinobenzyl ester are dissolved in 150 ml of chloroform and at 0 ° C.

8.2 ml of diisopropylamine are added. Then, 2.4 ml of ethyl chloroformate was added to the reaction mixture and the mixture was refluxed for 3 hours. The mixture was washed with 0.1 M hydrochloric acid and brine, dried and evaporated. The title compound is obtained as an amorphous material. The product is thin-layer chromium22

EN 219 343 Β in angiography (N3 system) shows a value of 0.45 R _r .

b) N- (Ethoxycarbonyl) -N - {[2 '- (1H-tetrazol-5-yl) biphenyl4-ylmethyl]} - (L) -valine benzyl ester

10.0 g of N-carboethoxy-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valinobenzyl ester and 9.2 g of tributyltin azide in 150 ml of o- and refluxed in xylene for 18 hours. The reaction mixture was concentrated and the residue was stirred with 5M hydrochloric acid for 15 minutes. Then evaporate again. The residue was dissolved in ether and extracted with cold 4 M potassium hydroxide. The aqueous phase was acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified by flash chromatography (250 g silica gel, N6 system). The title compound is obtained as an amorphous material. The product showed _Rf value of 0.22 on TLC (N6 system).

Example 65 (S) -N- (1-Carboxy-2-methylprop-1-yl) -N-propyloxycarbonyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl -4-ylmethyl] -amine

In a manner similar to that described in Example 1, 0.14 g of N- (propoxycarbonyl) N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} is obtained. Starting from (L) -valine in the presence of 0.07 g of Pd / C catalyst. The product is obtained after flash chromatography as an amorphous material (B1). FAB-MS: m / e 438 (M + H +).

For example, the starting material may be prepared as follows:

a) N- (Propoxycarbonyl) -N - [(2 '-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester

1.0 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester, 0.8 ml of diisopropylethylamine and 0.34 ml of chloroformate propyl ester and flash chromatography on N3. The product is an amorphous material, which shows 0.38 R _{r in} thin layer chromatography (N 2 system).

b) N- (Propoxycarbonyl) -N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} - (L) -valine benzyl ester

1.04 g of N- (propoxycarbonyl) -N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester and 1.1 g of tributyltin azide are reacted with Flash chromatography on N6 system. The product is swallowed as an amorphous material. TLC (N6 system) Rf = 0.21.

Example 66 (S) -N-Butyloxycarbonyl-N- (1-carboxy-2-methylpropyl) -N- [2 '- (1H-tetrazol-5-yl) biphenyl-4 yl-methyl] amine

In a manner similar to that described in Example 1, 0.40 g of N-butoxycarbonyl-N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl was prepared. } - (L) valine in the presence of 0.20 g of Pd / C catalyst. The product was obtained after flash chromatography (system B1) as an amorphous material. FAB-MS: m / e 452 (M + H +).

For example, the starting material may be prepared as follows:

a) N- (Butoxycarbonyl) -N - [(2 '-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester

The title compound was prepared from 1.0 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester, 0.8 ml of diisopropylethylamine and 0.34 ml of the title compound. Starting from 1 ml of chloroformic acid butyl ester, after flash chromatography (N3 system). The product is an amorphous material which, in a thin layer chromatography (N2 system), exhibits a value of 0.41 R.

b) N- (Butoxycarbonyl) -N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} - (L) -valine benzyl ester

The title compound was prepared by 1.05 g of N- (butoxycarbonyl) -N- [2'-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester and Tributyltin azide (05 g) was reacted and flash chromatographed (N6 system). The product was obtained as an amorphous material. TLC (N6 system) showed 0.17 R _r .

Example 67 (S) -N- (1-Carboxy-2-methylprop-1-yl) -N-methoxycarbonyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4 yl-methyl] amine

In a manner similar to that described in Example 1, 2.40 g of N- (methoxycarbonyl) -N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl is prepared. } - (L) valine in the presence of 0.50 g of Pd / C catalyst. After flash chromatography (B1), the product is swallowed as an amorphous material. FAB-MS: m / e 410 (M + H +).

For example, the starting material may be obtained as follows:

a) N- (Methoxycarbonyl) -N - [(2 '-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester

The title compound was prepared by 4.0 g of N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester, 3.3 ml of diisopropylethylamine and 0.78 ml methyl chloroformate was reacted and flash chromatographed (N3 system). The product is an amorphous material, which shows 0.34 R _{r in} N3 thin layer chromatography.

b) N- (Methoxycarbonyl) -N - {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} - (L) -valine benzyl ester

The title compound was obtained from 3.21 g of N- (methoxycarbonyl) -N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine benzyl ester and 3.50 g of tributyltin starting from azide, after flash chromatography (N6 system). The product is an amorphous material which R _r is the basis of thin layer chromatographic examination N6 0.26 respectively.

Example 68

In a similar manner to that described in Example 46, N- (2-diethylaminocarbonyl-2,2-tetramethylene-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl- 4-ylmethyl-amine is [R _f 0.47 (system N8)].

Example 69

In a similar manner to that described in Example 46, N- (2-methyl-2- (morpholin-4-ylcarbonyl) propyl) -Npentanoyl-N- [2 '- (1H-tetrazol-5-yl) - biphenyl-4-ylmethyl] amine in _[Rf 0.61 (system N8)].

HU 219 343 Β

Example 70

In a similar manner to that described in Example 63, N- (2-carboxy-2-methylpropyl) -N-pentanoyl-N- [2 '(1H-tetrazol-5-yl) biphenyl-4-ylmethyl may be prepared. ] as well as [R _f 0.39 (N8 system)].

Example 71

In a similar manner to that described in Example 39, N- (2-carboxy-2,2-pentamethylene-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-one can be prepared. il-methyl] -amine [R _f 0.33 (N8 system)].

Example 72

1.5 g (2.8 mmol) of N- (1-benzyloxycarbonyl-cyclopentyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] hydrogenated in 20 mL of dioxane with 0.3 g of Pd / C (10%) as in Example 56. Purification by flash chromatography on silica gel (S2 system) affords N- (1-carboxycyclopentyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-one as a foam. ilmethyl] -amine [R _f 0.29 (S2 system)].

For example, the starting material may be prepared as follows:

a) 2.72 g (10 mmol) of 4-bromomethyl-2'-cyanobiphenyl,

A mixture of 2.63 g (12 mmol) of 1-aminocyclopentanecarboxylic acid benzyl ester, 3.4 mL (20 mmol) of hygene base and 10 mL of Ν, Ν-dimethylformamide was heated at 130-140 ° C for 2 hours with stirring. C at boiling point. After cooling, the reaction mixture is poured into 50 ml of ice water. Extraction with ethyl acetate gives crude N- (1-benzyloxycarbonylcyclopentyl) -N- (2'-cyanobiphenyl-4-ylmethyl) amine, whose hydrochloride is recrystallized from ethanol / diethyl ether to give 180-182. ° C.

b) 2.9 g (5 mmol) of N- (1-benzyloxycarbonyl-cyclopentyl) -N- (2'-cyanobiphenyl-4-ylmethyl) -amine hydrochloride and

To a solution of Hygg's base (4.4 mL, 26 mmol) in ethyl acetate (50 mL) was added pentanoyl chloride (11.1 g, 9 mmol), and the reaction mixture was stirred at 25-30 for 15 h. After adding another 0.5 g of pentanoyl chloride, stirring was continued for 8 hours. 10 ml of 5% aqueous ammonia solution are then added and the mixture is stirred for 0.5 hour. The ethyl acetate layer was separated and washed successively with 2N hydrochloric acid, water and sodium bicarbonate solution, dried and evaporated. N- (1-Benzyloxycarbonylcyclopentyl) -N- (2'-cyanobiphenyl-4-ylmethyl) -n-pentanoylamine is obtained in the form of a brown oily substance [Rf 0.53; B7 system)]. The product was reacted further without purification.

c) 3.2 g (6.5 mmol) of N- (1-benzyloxycarbonyl-cyclopentyl) -N- (2'-cyano-biphenyl-4-ylmethyl) -N-pentanoylamine,

A mixture of tributyltin azide (3.3 g, 9.8 mmol) and o-xylene (35 g) was heated at reflux for 24 hours. The mixture was worked up in the same manner as in Example 23. N- (1-Benzyloxycarbonyl-cyclopentyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine is obtained in the form of a yellow oil. [R _f 0.37 (S2 system)]. The product was reacted further without purification.

Example 73

2.4 g (4.3 mmol) of N- (1-benzyloxycarbonyl-cyclohexyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] A solution of the amine in 40 mL of dioxane was hydrogenated with 0.5 g of Pd / C (10%) as described in Example 73. The resulting N- (lacarboxycyclohexyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine is a colorless crystalline material. The product recrystallized from ethyl acetate, m.p. 134-136 ° C.

For example, the starting material may be prepared as follows:

(a) N- (1-Benzyloxycarbonyl-cyclohexyl) -N- (2'-cyanobiphenyl-4-ylmethyl) -amine, whose hydrochloride, after recrystallization from isopropanol, m.p. It is obtained in a similar manner to that described in Example 73a).

b) 2.9 g (6.8 mmol) of N- (1-benzyloxycarbonylcyclohexyl) -N- (2'-cyanobiphenyl-4-ylmethyl) -amine and 4.4 ml of To a solution of Hygg's base (26 mmol) in ethyl acetate (50 mL) was added pentanoyl chloride (1.1 g, 9 mmol) and refluxed for 24 hours. The reaction mixture was cooled, added with 20 ml of 2N aqueous ammonia solution and stirred for 1 hour. The organic layer was separated and washed successively with 2N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried and evaporated. The resulting N- (1-benzyloxycarbonylcyclohexyl) -N- (2'-cyanobiphenyl-4-ylmethyl) -N-pentanoylamine is a brown oily substance [R _f 0.44 ( toluene / methanol 19: 1)]. The product was reacted further without purification.

c) 3.3 g (6.5 mmol) of N- (1-benzyloxycarbonyl-cyclohexyl) -N- (2'-cyano-biphenyl-4-ylmethyl) -N-pentanoylamine; A mixture of tributyltin azide (1 g, 12.3 mmol) and o-xylene (30 mL) was refluxed for 44 hours. The mixture was worked up in a similar manner to that described in Example 23. Thus, N- (1-benzyloxycarbonyl-cyclohexyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine is swallowed as a pale crystalline material. . After recrystallization from ethyl acetate / diethyl ether, m.p. 189-190 ° C.

Example 74

In a similar manner to that described in Example 73, N- (1-carboxy-1-ethyl-prop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl may be prepared. -4-ylmethyl] amine [light foam; R _f 0.35 (S2 system)].

Example 75

170 mg of (S) -N- (1-benzyloxycarbonyl-5-benzyloxycarbonylamino-pent-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) - biphenyl-4-ylmethyl] -amine is dissolved in 5 ml of methanol. To the solution was added 170 mg of Pd / C (10%) and the mixture was hydrogenated at room temperature under saturated pressure to room temperature. The reaction mixture was filtered through Hyflo and the filtrate was evaporated. Thus, pure (S) -N- (5-amino-1-carboxypent-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4] is obtained as a white foam. -ylmethyl] amine. [MS (FAB): m / z 465 (M + H +)].

For example, the starting material may be prepared as follows:

HU 219 343 Β

(a) Dissolve 5.0 g of (S) -2-amino-6-benzyloxycarbonylamino-hexanoic acid benzyl ester in 250 ml of N, N-dimethylformamide. To the solution was added 4.33 ml of N, N-diisopropyl-N-ethylamine, heated to 80 ° C, stirred for 30 minutes, followed by 4.44 g of 4-bromomethyl-2 '- (1-triphenylmethyl-1 tetrazol-5-yl) -biphenyl was added, the mixture was stirred at 80 ° C for 16 hours and then concentrated. The residue was treated with water and ethyl acetate. The organic phase was dried and purified by flash chromatography (200 g silica gel; N4 system). (S) -N- (1-Benzyloxycarbonyl-5-benzyloxycarbonylaminopentyl) -N- [2 '- (1-triphenylmethyl-1H-tetrazole-5-) obtained yl) -biphenyl-4-ylmethyl] amine brown oil form [R _f 0.18 (system N3)].

b) 1.1 g of (S) -N- (1-benzyloxycarbonyl-5-benzyloxycarbonylaminopent-1-yl) -N- [2 '- (1-triphenylmethyl-1H-tetrazole) -5-yl) -biphenyl-4-ylmethyl] -amine is dissolved in 20 ml of CH ₂ Cl ₂ . The solution was cooled to 0 ° C and N, N-diisopropyl-N-ethylamine (0.408 mL) was added followed by pentanoyl chloride (0.29 mL). The reaction mixture was stirred for 15 minutes under ice-cooling and then for 16 hours at room temperature. The mixture was diluted with CH ₂ Cl ₂ , washed successively with 1N sodium hydroxide solution, 1N hydrochloric acid, water and brine, and dried over magnesium sulfate. Purification by flash chromatography (200 g silica gel; N3 system) gave (S) -N- (1-benzyloxycarbonyl-5-benzyloxycarbonylaminopent-1-one) as a brownish oily substance. yl) -N-pentanoyl-N- [2 '- (1-triphenylmethyl-1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine [R _f 0.34 (in N2 system)] .

c) 1.07 g of (S) -N- (1-benzyloxycarbonyl-5-benzyloxycarbonylamino-pent-1-yl) -N-pentanoyl-N- [2 '- (1) -triphenylmethyl-1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine is dissolved in 15 ml of dioxane. To this solution was added 1.5 mL of 7N hydrochloric acid in dioxane and stirred for 4.5 hours at 40 ° C. The reaction mixture was evaporated and purified by flash chromatography (200 g silica gel; N6 system). Thus, (S) -N- (1-benzyloxycarbonyl-5-benzyloxycarbonylaminopent-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) - biphenyl-4-ylmethyl] amine is obtained [R _f 0.42 (system N7)].

Example 76

3.64 g of N-butanesulfonyl-N- (2'-cyanobiphenyl-4-ylmethyl) -N- (2-ethoxycarbonyl-2,2-pentamethylene-ethyl) -amine, 5.0 g of tributyl- a mixture of tin azide and 20 ml o-xylene is refluxed for 15 hours. The reaction mixture was cooled and evaporated. To the residue was added 20 mL of 3N hydrochloric acid in methanol, stirred for 1 hour and evaporated. The residue was taken up in diethyl ether. The ethereal solution was extracted with 1N sodium hydroxide solution. The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (220 g silica gel; CH ₂ Cl ₂ / acetone 9: 1). Crystallization from pentane gives N-butanesulfonyl-N- (2-ethoxycarbonyl-2,2-pentamethylene-ethyl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl ], which melts at 121 ° C with decomposition.

For example, the starting material may be prepared as follows:

(a) Dissolve 3.0 g of 1-aminomethyl-1-ethoxycarbonyl-cyclohexane in 25 ml of CH ₂ Cl ₂ . Butane sulfonyl chloride (0.7 mL) was added to the solution at room temperature. The reaction mixture was refluxed for 5 hours and evaporated after cooling. The residue was taken up in diethyl ether. The ether layer was successively extracted with 1N hydrochloric acid and water, dried over magnesium sulfate and evaporated. The yellow waxy residue of crude N-butanesulfonyl-N- (2-carboethoxy-2,2-pentamethylene-ethyl) -amine _[Rf 0.65 (system N2)], which was further reacted without purification.

b) N-Butanesulfonyl-N- (2-ethoxycarbonyl-2,2-pentamethylene-ethyl) -amine (3.75 g) is dissolved in THF (30 mL). The solution was cooled in an ice bath and 309 mg of sodium hydride dispersion (80% in oil) was added. After heating, 3.5 g of 4-bromomethyl-2'-cyanobiphenyl are added to the reaction mixture, which is stirred for 30 hours at room temperature and for 4 hours at 60 ° C and evaporated after cooling. The residue was taken up in diethyl ether. The ether phase was successively extracted with 1N hydrochloric acid and water, dried and evaporated. The residue was subjected to flash chromatography (300 g on silica gel; hexane / tert-butyl methyl ether 4: 1) to give pure N-butanesulfonyl-N- (2'-cyanobiphenyl-4-ylmethyl) -N- (2-ethoxy). carbonyl-2,2-pentamethylene-ethyl) -amine was obtained as a yellow resin [R _f 0.46 (hexane / tert-butyl methyl éter4: 1)].

Example 77

1.8 g of N-butanesulfonyl-N- (2-ethoxycarbonyl-2,2-pentamethylene-ethyl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine 50 ml of 1: 1 methanol / water. To the mixture was added 5.0 g of sodium hydroxide and the mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid, saturated with sodium chloride and extracted with CH ₂ Cl ₂ . The combined organic layers were dried and evaporated. Recrystallized from diethyl ether / hexane to give pure N-butanesulfonyl-N- (2-carboxy-2,2-pentamethylene-ethyl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] ], which melts at 123 ° C with decomposition.

Example 78

In a similar manner to that described in Example 76, N-butanesulfonyl-N- (2-ethoxycarbonyl-2-methylprop-1-yl) -N- [2 '- (1H-tetrazol-5-yl) may be prepared. -biphenyl-4-ylmethyl] amine. The product melts at 104 ° C.

Example 79

The ΊΊ. In a similar manner to that described in Example 1b, N-butanesulfonyl-N- (2-carboxy-2-methylpropyl) -N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl may be prepared. -methyl] -amine, m.p. 137 ° C.

HU 219 343 Β

Example 80

In a similar manner to that described in Example 76, (S) -N-butanesulfonyl-N- (1-tert-butoxycarbonylethyl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl- 4-ylmethyl] -amine, using (S) -2-aminopropanoic acid tert-butyl ester as starting material.

Example 81

750 mg (S) -N-butanesulfonyl-N- (1-tert-butoxycarbonyl-ethyl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] as treated with 1.9N glacial acetic acid for 24 hours. The reaction mixture was concentrated and the residue was subjected to flash chromatography (100 g silica gel; CH ₂ Cl ₂ / ethyl acetate / toluene / formic acid 40: 40: 20: 4). Thus, (S) -N-butanesulfonyl-N- (1-carboxyethyl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] is swallowed as a white amorphous powder. methyl] -amine, which melts at 90 ° C and decomposes at 127 ° C.

Example 82

In the same manner as in Examples 76 and 37, (S) -N-butanesulfonyl-N- (1-aminocarbonyl-2-methylprop-1-yl) -N- [2 '- ( 1H-Tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine (melting point 103 ° C); starting with (S) -2-amino-3-methylbutanoic acid benzyl ester p-toluenesulfonate.

Example 83

In a similar manner to that described in Example 47, (S) -N- (1-aminocarbonyl-2-methylprop-1-yl) -Npentanoyl-N- [2 '- (1H-tetrazol-5-yl) may be prepared. ) -biphenyl-4-ylmethyl] -amine; mp 177-178 ° C.

Example 84

In a similar manner to that described in Example 47, (S) -N- (2-methyl-1-methylaminocarbonylpropyl-N) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-one) may be prepared. -yl) -biphenyl-4-ylmethyl] -amine; mp 183-184 ° C.

Example 85

In a similar manner to that described in Example 47, (S) -N- (1-Dimethylaminocarbonyl-2-methylpropyl-N) -N-pentanoyl-N- [2 '- (1H-tetrazole-5-one) may be prepared. -yl) -biphenyl-4-ylmethyl] -amine; mp 179-180 ° C.

Example 86

In a similar manner to that described in Example 47, (S) -N- (2-methyl-1-morpholin-4-ylcarbonylpropyl) -N-pentanoyl-N- [2 '- (1H-tetrazole) can be prepared. -5-yl) -biphenyl-4-ylmethyl] -amine; the product melts at 130 ° C with decomposition.

Example 87

In a similar manner to that described in Example 8, (S) -N- (2'-Carboxy-biphenyl-4-ylmethyl) -N- (1-carboxy-2-methyl-prop-1-yl) -N can be prepared. also pentanoylamine; mp 66-68 ° C.

Example 88

In a similar manner to that described in Example 16, (S) -N- (1,2-dicarboxyethyl) -N-pentanoyl-N- [2 '(1H-tetrazol-5-yl) -biphenyl-4-yl] can be prepared. -methyl] as well as; the product

303-305 ° C.

Example 89

In a similar manner to that described in Example 16, (S) -N- (1-Carboxy-2-methylprop-1-yl) -N- (5-oxopent-1-en-5-yl) -N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine; mp 108-109 ° C.

Example 90

Similarly to the procedures described above, the following compounds may be prepared:

1. (S) -N- (1-Carboxy-3-phenylprop-1-yl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl ] -amine (m.p. 124-125 ° C);

2. (S) -N- (2-Cyclohexyl-1-hydroxymethyl-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] amine (m.p. 86-87 ° C);

3. (R) -N- (1-Methoxycarbonyl-2-methyl-prop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4- ylmethyl] -amine (m.p. 77-78 ° C);

4. (S) -N- (1-Carboxy-4-guanidino-but-1-yl) -N-pentanoyl-N - [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] amine hydrochloride; [R _f 0.34 (CH ₂ Cl ₂ / CH ₃ OH / Conc. Ammonia 20: 10: 1)];

5. N- (1-Benzyloxycarbonyl-1-methylethyl) -N-butanoylN- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine (a) mp 203-204 ° C);

6. (S) -N- (1-Carboxy-3-methyl-but-1-yl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl ] -amine (product melting point:> 300 ° C);

7. (S) -N- [2-Methyl-1- (2-phenylethylaminocarbonyl) -propl-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) Biphenyl-4-ylmethyl] -amine (m.p. 109-110 ° C);

8. (S) -N- (1-Carboxy-2-methyl-prop-1-yl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) -biphenyl-3-ylmethyl ] -amine (product m.p. 78-79 ° C);

9. (S) -N- (1-Carboxy-2-methyl-prop-1-yl) -N-pentanoyl-N [3 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl ] -amine (product m.p. 97-98 ° C);

10. (S) -N- [2-Methyl-1- (1,2,3,4-tetrahydro-quinol-1-yl-carbonyl) -prop-1-yl] -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine (m.p. 100-110 ° C);

11. (S) -N- (2-Methyl-1-piperidin-1-yl-carbonyl-prop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl -4-ylmethyl] -amine (m.p. 100 ° C);

12. (S) -N- [2-Methyl-1- (1,2,3,4-tetrahydro-isoquinol-2-ylcarbonyl) -prop-1-yl] -N-pentanoyl-N- [2 '- (1 H -tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine (m.p. 122 ° C);

13. N- (2-Hydroxymethyl-2-methyl-prop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine [R _f 0.45 (CH ₂ Cl ₂ / CH ₃ OH 4: 1)];

14. N-Ethoxycarbonyl-N- (2-ethoxycarbonyl-2-methylprop-1-yl) -N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amine [R _f 0.64 (CH ₂ Cl ₂ / CH ₃ OH 4: 1)]; and

15. N- (2-Carboxy-2-methyl-prop-1-yl) -N-ethoxycarbonyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] - amine [R _f 0.32 (CH ₂ Cl ₂ / CH ₃ OH 4: 1)].

HU 219 343 Β

Example 91

For example, (S) -N- (lacarboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-one (50 mg) each. Tablets containing il-methyl] -amine can be prepared, for example, as follows: Composition (for 10,000 tablets):

Active ingredient 500.0 g

Lactose 500.0 g

Potato starch 352.0 g

Gelatin 8.0 g

Talcum 60.0 g

Magnesium stearate 10.0 g

Silica (high dispersion) 20.0 g

Ethanol as needed

The active ingredient is mixed with lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. The granulate is dried and then mixed with the remaining potato starch, talc, magnesium stearate and highly dispersed silica, and the mixture contains 145.0 mg and 50.0 mg of active ingredient each, if desired for finer dosing. - compressed into scored pills.

Example 92

Each 100 mg of active ingredient, for example, (S) -N- (lacarboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4] For example, lacquered tablets containing -ylmethyl] -amine may be prepared as follows:

Composition (per 1000 tablets):

Active ingredient 100.00 g

Lactose 100.00 g 35

Corn starch 70.00 g

Talc 8.50 g

Calcium stearate 1.50 g

Hydroxypropylmethyl cellulose 2.36 g

Shellak 0.64 g 40

Water as needed

Dichloromethane as needed

The active ingredient is mixed with lactose and 40 g of corn starch and the mixture is moistened and granulated with 45 g of corn starch and 15 g of water while heating. The granulate is dried and mixed with residual corn starch, talc and calcium stearate. The mixture is then compressed into 280 mg tablets each and lacquered with a solution of hydroxypropylmethyl cellulose and shellac in 50 dichloromethane. The final weight of the lacquered tablets is 283 mg.

Example 93

Similar to the procedure described in Examples 92 and 93, tablets and lacquered tablets other than those described in Examples 1-91 may be prepared. A compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) prepared according to any one of Examples 1 to 6, as active ingredient. 60

Claims (45)

PATENT CLAIMS A process for the preparation of a compound of formula (I) R 1 is lower alkyl or lower alkenyl; X 1 = CO, = SO ₂ or -OC (= O) - wherein the carbon atom of the carbonyl group is attached to the nitrogen atom indicated in the compound of formula (I); X _{2 is} C 1 -C 10 alkylene or C 2 -C 10 alkylidene optionally substituted by hydroxy, carboxy, amino, guanidino, C 3 -C 7 cycloalkyl or imidazolyl optionally substituted by phenyl, optionally substituted by halogen; one or more carbon atoms of alkylene or C2-C10 alkylidene It may be bridged with a C 2 -C 6 alkylene group; or represents a C3-C7 cycloalkylene group, R _{2 is} mono-or disubstituted or optionally substituted with lower alkyl or phenyl-lower alkyl, optionally substituted with lower alkyl or phenyl-lower alkyl, optionally substituted with lower alkyl or lower hydroxy; substituted carbamoyl; morpholinocarbonyl, C3-7 alkyleneiminocarbonyl, tetrahydroquinol-1-ylcarbonyl, tetrahydroisoquinol-2-ylcarbonyl, lower alkanoylamino, hydroxy, lower alkoxy, phenyl lower alkoxy or phenoxy; X ₃ lower alkylene; R _{3 is} carboxy or 5-tetrazolyl; Ring A is optionally substituted even with halogen, and the lower radicals have up to 7 carbon atoms and the lower alkenyl group has 2 to 7 carbon atoms free or in salt form, characterized in that (a) a compound of formula II or a salt thereof, wherein Z 1 is a functionally modified carboxy group, preferably lower alkoxycarbonyl, tri (C 1 -C ₄ ) alkylsilyl (C 1 -C ₄ ) alkoxycarbonyl or cyano, Z _{3 is} R _3; or (b) in a compound of formula (II) or a salt thereof, when Z 1 is a protected 5-tetrazolyl group, by converting a protecting group into a R ₃ 5-tetrazolyl group, or (c) in a compound of formula (II) or a salt thereof, when Z 1 is cyano, reacting Z 1 with an azide to R ₃ 5 -tetrazolyl, or (d) reacting a compound of formula (I) or a salt thereof; wherein the R ₂ is a carboxy group, the ester is decomposed in a compound of formula (I) wherein R ₂ is an esterified carboxy group, or (e) to produce a compound of formula (I) wherein R ₂ is a an esterified carboxy group of the present invention, esterifying a compound of formula I wherein R ₂ is a carboxy group, (F) amidating a compound of formula (I) wherein R ₂ is an amidated carboxy group, to prepare a compound of formula (I) wherein R ₂ is carboxy; For the preparation of a compound of formula I or a salt thereof wherein R ₂ is a hydroxymethyl group with a methylene group of X ₂ , a compound of formula I wherein R ₂ is optionally an esterified carboxy group is reduced by the appropriate reducing agent; h) for the preparation of a compound of formula (I) or a salt thereof wherein R ₂ is a hydroxymethyl group with a methylene group of X ₂ , the ether is decomposed in a compound of formula (I) wherein R ₂ is an etherified hydroxy group; or a salt thereof The compound of formula (I) obtained according to the present invention is converted into a free compound of the formula (I) or another salt. 2. A process for the preparation of a compound of formula (I): wherein R 1 is lower alkyl or lower alkenyl; X 1 = CO or = SO ₂ ; X ₂ is phenyl optionally substituted with hydroxy, a C 3 -C 7 cycloalkyl or imidazolyl, optionally substituted with halogen C 1 -C 10 alkylene or C 2 -C 10 alkylidene, wherein C 1 -C 10 alkylene or In addition, one carbon atom of a C2-C10 alkylidene group may be bridged with another C2-C6 alkylene group; obsession X ₂ is C 3 -C 7 cycloalkylene, R _{2 is} a carboxyl group optionally esterified with an alcohol containing a lower alkyl or a phenyl (lower) alkyl group, a carbamoyl group optionally substituted by a lower alkyl group, mono- or disubstituted or optionally substituted by a hydroxy group. ; morpholinocarbonyl, C3-C7 alkyleneiminocarbonyl, lower alkanoylamino, hydroxy, lower alkoxy, phenyl (lower) alkoxy or phenoxy; X ₃ is a lower alkylene group; R _{3 is} carboxy or 5-tetrazolyl; Ring A is optionally even substituted with halogen, and the lower radicals have up to 7 carbon atoms, even for the preparation of the lower alkenyl radical in the form of 3 to 7 carbon atoms free or in salt, characterized in that (a) a compound of formula II or a salt thereof, wherein Z 1 is a functionally modified carboxy group, preferably lower alkoxycarbonyl, tri- (C 1 -C ₄ ) alkylsilyl (C ₁ -C ₄ ) alkoxycarbonyl or cyano, Z ₍ R is converted to _three carboxy group, or (b) a compound (II) or a salt thereof, if Zj is a protected 5-tetrazolyl, Z _r et deprotected converted to R ₃ 5-tetrazolyl, or (c) a (II) compound or salt thereof when Z is a cyano group, Z _r et reacted with an azide is converted to R ₃ 5-tetrazolyl, or (d) a compound (I) or formula s ja thereof, wherein R ₂ is carboxy, a compound (I) wherein R ₂ is an esterified carboxyl group stated above, the ester is decomposed, (e) a compound (I) or salt thereof of formula wherein R ₂ is esterifying an esterified carboxy group of a compound of formula (I) wherein R ₂ is a carboxy group; (f) preparing a compound of formula (I) or a salt thereof wherein R ₂ is an amidated carboxy group of formula (I); Amidating a compound of formula I wherein R ₂ is a carboxy group, (g) producing a compound of formula I or a salt thereof wherein R ₂ is a hydroxymethyl group with a methylene group of X ₂ , a compound of formula I, wherein R ₂ is an optionally esterified carboxy group with a suitable reducing agent induced (h) reacting a compound (I) or a salt thereof, wherein R ₂ is X ₂ is a methylene of a hydroxymethyl group in a compound of formula (I) wherein R ₂ is etherified hydroxy, ether is decomposed and optionally converting a free base of a compound of formula (I) according to the invention to a salt or converting a compound of formula (I) obtained in the form of a salt of this invention into a free compound of formula (I) or another salt. 3. A process for the preparation of a compound of formula I wherein: R 1 is lower alkyl or lower alkenyl; X 1 = CO or = SO ₂ ; X ₂ is C 1 -C 10 alkylene or C 2 -C 10 alkylidene optionally substituted by hydroxy, C 3 -C 7 cycloalkyl or imidazolyl optionally substituted by phenyl optionally substituted by halogen; R _{2 is} a carboxyl group optionally esterified with an alcohol containing a lower alkyl or phenyl lower alkyl group, a carbamoyl group optionally substituted with a lower alkyl group, mono- or disubstituted or optionally substituted with a hydroxy group. ; morpholinocarbonyl, C3-C7 alkyleneiminocarbonyl, lower alkanoylamino, hydroxy, lower alkoxy, phenyl (lower) alkoxy or phenoxy; X _{3 is} -CH ₂ -; R _{3 is} carboxy or 5-tetrazolyl; Ring A is optionally substituted even with halogen, and the lower radicals have up to 7 carbon atoms, even the lower alkenyl radical In a free form or in the form of a salt having from 3 to 7 carbon atoms, characterized in that (a) in a compound of formula II or a salt thereof, wherein Z 1 is a functionally modified carboxy group, preferably lower alkoxycarbonyl, tri- (C 1 -C ₄ ) alkylsilyl (C 1 -C ₄ ) alkoxycarbonyl or cyano, converting Z _{2 to} R ₃ carboxy, or (b) in a compound of formula (II) or a salt thereof when Z 1 is protected 5-tetrazolyl , Zj was deprotected converted to R ₃ 5-tetrazolyl, or (c) a compound (II) or a salt thereof, if Z₁ is cyano, Zj was reacted with an azide is converted to R ₃ 5-tetrazolyl, or ( d) for the preparation of a compound of formula (I) or a salt thereof wherein R ₂ is carboxy, in a compound of formula (I) wherein R ₂ is an esterified k arboxyl, the ester is decomposed, (e) esterification of a compound of formula (I) wherein R ₂ is an esterified carboxy group, a compound of formula (I) wherein R ₂ is carboxy, (f) to amidate a compound of formula (I) wherein R ₂ is an amidated carboxy group, to obtain a compound of formula (I) wherein R ₂ is carboxy, (g) reacting a compound of formula (I) or a salt thereof wherein R ₂ is a hydroxymethyl group with a methylene group of X ₂ , reducing a compound of formula I wherein R ₂ is an optionally esterified carboxy group with a suitable reducing agent; or (h) preparing a compound of formula I or a salt thereof. wherein R ₂ is a hydroxymethyl group with a methylene group of X ₂ , e In a compound of formula (I) wherein R ₂ is an etherified hydroxy group, the ether is decomposed and, if desired, a free base of a compound of formula (I) prepared according to the invention or a compound of formula (I) To a compound of formula (I) or to another salt. Process (a) according to Claim 3, characterized in that the compound of the formula (II) in which Zi is tri- (C 1 -C 4) alkylsilyl- (C 1 -C 4) -alkoxy- is used. carbonyl such as trimethylsilyl ethoxycarbonyl; and the protecting group is cleaved in the presence of a base such as tetraalkylammonium halide such as tetrabutylammonium fluoride. Process (b) according to claim 3, characterized in that the compound of formula (II) in which Z 1 is a triphenylmethyl protected 5-tetrazolyl group is started and the protecting group is cleaved in the presence of an acid. Process (c) according to claim 3, characterized in that the compound of the formula (II) in which Z 1 is a cyano group is started and this compound is reacted with an azide, such as tri- (lower) alkylone azide such as tributyltin azide. 7. A compound according to claim 3, process (g), characterized by starting from a compound of formula (I) wherein R ₂ is benzyloxy carbonyl group, and Ester is a hydrogenation catalyst such as palladium / C in the presence of finally. 8 (d) A method according to claim 3, characterized in that starting from a compound of formula (I) wherein R ₂ represents a tert-butoxycarbonyl group, and Ester carried out by acidolysis, such as acetic acid. A process for the preparation of a compound of formula (I) and salts thereof according to claim 2, wherein R 1, R ₂ , R ₃ , X ₁ and X ₂ are as defined in claim 2, X _{2 is} optionally hydroxy, a 3-7 compound. cycloalkyl, imidazolyl, substituted lower alkylene or lower alkylidene, or _X2 is lower alkylene substituted by halogen phenyl optionally substituted, whereby a carbon bridged a C2-6 alkylene, or C3-7 cycloalkylene, and The ring may be optionally substituted even with a halogen atom, characterized in that the appropriate starting materials are used. 10. Referring to FIGS. A process for the preparation of compounds of formula (Ia) and salts thereof according to any one of claims 1 to 6, wherein R 1, X ₁ , X ₂ , R ₂ and R _{3 have} the meanings given in claim 3 and ring A is optionally substituted even with a halogen atom, wherein the appropriately substituted starting materials are used. A process for the preparation of a compound of formula (Ia) and salts thereof according to claim 2, wherein X _{2 is} C 1 -C 10 alkylene or C 2 -C 10 acylidene optionally substituted with hydroxy or a 3 to 7 membered cycloalkyl group, wherein one carbon atom of the lower alkylene or lower alkylidene group may be bridged with C 2 -C 6 alkylene, or wherein X _{2 is C} 3 -C 7 cycloalkylene, and R 1, X 1, R ₂ and R _{3 are} as defined in claim 2 and Ring A is optionally substituted with halogen, wherein the appropriately substituted starting materials are used. 12. In Figure 3-8. A process according to any one of claims 1 to 10 and 10 for the preparation of a compound of formula (Ia) and salts thereof, wherein X ₂ represents a group of formula (Ib) wherein p is 0 or 1, q is 1 and r is 0 or 1, or wherein p is 1-8 and q and r are both 0; HU 219 343 Β X _{4 is} a lower alkyl or phenyl optionally substituted with hydroxy, a 3-7 membered cycloalkyl, phenyl or imidazolyl, and X _{5 is} hydrogen or lower alkyl; with the proviso that the number of carbon atoms in the alkyl group in X ₂ may not exceed 10; R _{2 is} carboxy, lower alkoxycarbonyl, phenyl (lower) alkoxycarbonyl, hydroxy, lower alkoxy, phenyl (lower) alkoxy, phenoxy, or lower alkanoylamino. ; and R _{b is} X [and R _{3 is} as defined in claim 3; and Ring A is optionally substituted with halogen, wherein the appropriately substituted starting materials are used. A process according to any one of claims 2 and 11 for the preparation of compounds of formula (Ia) and salts thereof, wherein: X ₂ represents a group of formula (Ib) wherein p is 0 or 1, q is 1 and r is 0 or 1, or wherein p is 1-8 and q and r are both 0; X _{4 is} lower alkyl or phenyl optionally substituted with hydroxy, a 3-7 membered cycloalkyl, phenyl or imidazolyl, and X _{5 is} hydrogen or lower alkyl; obsession X ₄ and X ₅ together represent an alkylene group having from 2 to 6 carbon atoms, in particular from 4 to 5 carbon atoms, with the proviso that the number of carbon atoms in the alkyl group in X ₂ may not exceed 10, or X _{2 is} 3-7, especially C 5 -C 6 cycloalkylene, R _{2 is} carboxy, lower alkoxycarbonyl, phenyl (lower) alkoxycarbonyl, hydroxy, lower alkoxy, phenyl (lower) a) alkoxy, phenoxy or lower alkanoylamino; and R _b Χ and R _{3 are} as defined in claim 2; and Ring A is optionally substituted with halogen, wherein the appropriately substituted starting materials are used. A process according to any one of claims 2 and 11 for the preparation of compounds of formula (Ia) and salts thereof, wherein: R 1 is lower alkyl, especially C 3 -C 5 alkyl, or lower alkenyl, especially C 3 -C 5 alkenyl; Xi a = CO and also = SO ₂ ; X ₂ (b) a group of formula wherein p and r is 0 or 1 and q is 1; X _{4 is} a lower alkyl such as C 1-4 alkyl or phenyl optionally substituted by hydroxy, a 3-7 membered cycloalkyl such as cyclohexyl, optionally substituted by halogen, or imidazolyl such as 4-imidazolyl; X ₅ is hydrogen or lower alkyl, e.g. C1-4 alkyl or X ₄ and X ₅ together form a C 2 -C 6, such as C 4 -C 5 alkylene, with the proviso that the number of carbon atoms in the alkyl group in X ₂ may not exceed 10; X ₂ C 3-7, for example, C5-6 cycloalkylene such as 1,4-cyclohexylene; R _{2 is} carboxy, lower alkoxycarbonyl, for example C2 -C5 alkoxycarbonyl, phenyl-lower alkoxycarbonyl such as phenyl (C1-C4) alkoxycarbonyl, hydroxy or lower alkoxy such as 1-4 alkoxy; R _{3 is} carboxy or 5-tetrazolyl; and Ring A is optionally substituted with halogen, wherein the appropriately substituted starting materials are used. 15. A process according to any one of claims 1 to 10 and 10 for the preparation of a compound of formula (Ia) and salts thereof, wherein R is lower alkyl, especially C 3-5 alkyl, or lower alkenyl, especially C 3-5 alkenyl; X, a = CO, and = SO ₂ ; X ₂ (b) a group of formula wherein p and r is 0 or 1 and q is 1; X _{4 is} a lower alkyl such as C 1-4 alkyl or phenyl optionally substituted by hydroxy, a 3-7 membered cycloalkyl group such as cyclohexyl, optionally substituted by halogen, or imidazolyl such as 4-imidazolyl, X ₅ is hydrogen or lower alkyl, e.g. C 1 -C 4 alkyl, provided that the number of carbon atoms in the alkyl group in X ₂ is not more than 10; R _{2 is} carboxy, lower alkoxycarbonyl, for example C2 -C5 alkoxycarbonyl, phenyl-lower alkoxycarbonyl such as phenyl (C1-C4) alkoxycarbonyl, hydroxy or lower alkoxy such as 1-4 alkoxy; R _{3 is} carboxy or 5-tetrazolyl; and Ring A is optionally substituted with halogen, wherein the appropriately substituted starting materials are used. 16. A 3-8. A process according to any one of claims 1 to 10 and 10 for the preparation of a compound of formula (Ia) and salts thereof, wherein R is lower alkyl, especially C 3-5 alkyl, or lower alkenyl, especially C 3-5 alkenyl; X] = CO and also = SO ₂ , X ₂ represents a group of formula (Ib) wherein p is 1-8 and q and r is 0, R ₂ hydroxy, lower alkoxy, for example C1 -C4 alkoxy, phenyl (lower) alkoxy such as phenyl (Cl-C4) alkoxy, fenoxivagy lower alkanoylamino, e.g. C2-C4 alkanoylamino, R _{3 is} carboxy or especially 5-tetrazolyl; and Ring A is optionally substituted with halogen, wherein the appropriately substituted starting materials are used. HU 219 343 Β A process according to any one of claims 2 and 11 for the preparation of compounds of formula (Ia) and salts thereof, wherein R 1 is C 3 -C 5 alkyl or C 3 -C 5 alkenyl; X! = CO and also = SO ₂ , X ₂ is a group of formula Ib wherein p and r are independently 0 or 1 and q is 1; X4 is (C1-C4) alkyl such as methyl, ethyl, propyl, isopropyl, 1- or 2-butyl, hydroxy (C1-C4) alkyl such as hydroxymethyl, 3-7; C 1 -C 4 cycloalkyl-C 1 -C 4 alkyl-such as cyclohexylmethyl, phenyl-C 1 -C 4 -alkyl such as benzyl, or imidazolyl-C 1 -C 4 alkyl such as imidazole; -4-yl-methyl; _X5 is hydrogen or C1-4 alkyl, such as methyl, or X ₄ and X ₅ together form a tetramethylene or pentamethylene group; R _{2 is} carboxy or C 2 -C 5 alkoxycarbonyl, or phenyl (C 1 -C 4) alkoxycarbonyl such as benzyloxycarbonyl, _R5 is carboxyl or primarily 5-tetrazolyl group, characterized in that correspondingly substituted starting materials are used. 18. A process according to any one of claims 1 to 10 and 10 for the preparation of a compound of formula (Ia) and salts thereof, wherein R 1 is C 3 -C 5 alkyl or C 3 -C 5 alkenyl; X 1 = CO and also = SO ₂ ; X ₂ is a group of formula Ib wherein p and r are both 0 or 1 and q is 1; X _{4 is C} 1 -C 4 alkyl such as methyl, ethyl, propyl, isopropyl, 1- or 2-butyl, hydroxy (C 1 -C 4) alkyl such as hydroxymethyl, C 7 -cycloalkyl (C 1 -C 4) -alkyl such as cyclohexylmethyl, phenyl (C 1 -C 4) -alkyl such as benzyl, or imidazolyl (C 1 -C 4) -alkyl e.g. imidazol-4-yl-methyl; X is ₅ hydrogen atoms, R _{2 is} carboxy or C 2 -C 5 alkoxycarbonyl, or phenyl (C 1 -C 4) alkoxycarbonyl such as benzyloxycarbonyl; R _{3 is} carboxy or 5-tetrazolyl; characterized in that the appropriately substituted starting materials are used. 19. A process according to any one of claims 1 to 10 and 10 for the preparation of a compound of formula (Ia) and salts thereof, wherein R) C 3 -C 5 alkyl, such as propyl, butyl or pentyl, Xj a = CO; X ₂ represents a group of the formula Ib wherein q and r are 0 and p is 1-3, especially 2, or wherein p and q are 1 and r is 0; X _{4 is C} 1 -C 4 alkyl such as methyl, ethyl, propyl, isopropyl, 1- or 2-butyl; _X5 is hydrogen or C1 -C4 alkyl, such as methyl; R _{2 is} carboxy or C 2 -C 5 alkoxycarbonyl such as methoxy or ethoxycarbonyl; R _{3 is} carboxy or 5-tetrazolyl, wherein the appropriately substituted starting materials are used. 20. In Figure 3-8. A process according to any one of claims 1 to 10 and 10 for the preparation of a compound of formula (Ia) and salts thereof, wherein R j is C 3 -C 5 alkyl, such as propyl, butyl or pentyl, Xj a = CO; X ₂ represents a group of formula Ib wherein p is 0 or 1, r is 0 and q is 1; X _{4 is C} 1 -C 4 alkyl such as methyl, ethyl, propyl, isopropyl, 1- or 2-butyl; _X5 is hydrogen or C1-4 alkyl, for example methyl or ethyl; R _{2 is} carboxy, C 2 -C 5 alkoxycarbonyl, such as methoxy or ethoxycarbonyl; and R _{3 is} carboxy or 5-tetrazolyl, wherein the appropriately substituted starting materials are used. A process according to any one of claims 2 and 11 for the preparation of compounds of formula (Ia) and salts thereof, wherein R j is C 3 -C 5 alkyl, such as propyl, butyl or pentyl, Xj a = CO; X ₂ is a group of formula Ib wherein p is 0 or 1, r is 0 and q is 1; X ₄ and X ₅ together form a tetramethylene or pentamethylene group; R _{2 is} carboxy or C 2 -C 5 alkoxycarbonyl such as methoxy or ethoxycarbonyl; R _{3 is} 5-tetrazolyl, wherein the appropriately substituted starting materials are used. 22. In Figures 3-8. A process according to any one of claims 1 to 10 and 10 for the preparation of a compound of formula (Ia) and salts thereof, wherein Rj is a C3-C5 alkyl group such as propyl, butyl or pentyl, Xj = CO, X ₂ is a group of formula Ib wherein p and r are 0 or 1 and q is 1, X _{4 is a C} 1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, 1- or 2-butyl, X is ₅ hydrogen atoms, R _{2 is} carboxy or C 2 -C 5 alkoxycarbonyl, such as methoxy or ethoxycarbonyl, and R _{3 is} 5-tetrazolyl, wherein the appropriately substituted starting materials are used. 23. A 3-8., 10, 12, 15, 16, 18-20. A process for the preparation of a compound of formula (I) or (Ia) of S configuration according to any one of claims 1 to 22 and 22, wherein the appropriate starting materials are used. A method according to any one of claims 2, 9, 11, 13, 14, 17 and 21 in an S configuration (I) or EN 219 343 Β, wherein the appropriate starting materials are used. 25. A process according to claim 1 for the preparation of a compound of formula (I) or (Ia) having the S configuration, wherein the appropriate starting materials are used. 26. Figures 3-8. A process according to any one of claims 1 to 4, which is (S) -N- (1-carboxyethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine or a salt thereof, wherein the appropriately substituted starting materials are used. 27. Referring to FIGS. A process according to any one of claims 1 to 4, wherein (S) -N- (1-Carboxy-2-methylprop-1-yl) -N-pentanoyl-N [2 '- (1H-tetrazol-5-yl) -biphenyl-4 ylmethyl] -amine or one of its salts, characterized in that the appropriately substituted starting materials are used. 28. A process for the preparation of N- (2-hydroxyethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine or a salt thereof according to any one of claims 1 to 4 to use appropriately substituted starting materials. The process according to claim 2, which is N- (2-ethoxycarbonyl-2,2-tetramethylene-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl ] -amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. 30. The process according to claim 2, which is N- (2-carboxy-2,2-tetramethylene-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] - amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. 31. Figures 3-8. A process according to any one of claims 1 to 4, which is N- (2-ethoxycarbonyl-2-ethyl-but-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4 ylmethyl] -amine or one of its salts, characterized in that the appropriately substituted starting materials are used. 32. A process according to claim 2 which is N- (2-ethoxycarbonyl-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4 -ylmethyl] -amine or a salt thereof, wherein the appropriately substituted starting materials are used. 33. The process according to claim 2, which is (S) -N- (1-hydroxymethyl-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazole-5-yl) -N yl) -biphenyl-4-ylmethyl] -amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. 34. The process according to claim 2, which is N- (2-ethoxycarbonyl-2,2-pentamethylene-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl ] -amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. The process according to claim 2, which is N- (2-carboxy-2-ethyl-but-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl. -methyl] -amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. 36. The process according to claim 2, which is (S) -N- (1-Carboxy-2-methylprop-1-yl) -N- (ethoxycarbonyl) -N- [2 '- (1H-tetrazole-5-yl) -5-. yl) -biphenyl-4-ylmethyl] -amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. The process according to claim 2, which is (S) -N- (1-carboxymethylprop-1-yl) -N- (propyloxycarbonyl) -N- [2 '(1H-tetrazole-5) -yl) -biphenyl-4-ylmethyl] -amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. 38. The process of claim 2, which is N- (2-carboxy-2-methylpropyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) bifem-4-ylmethyl] -amine. or a salt thereof, wherein the appropriately substituted starting materials are used. 39. The process according to claim 2, which is N- (2-carboxy-2,2-pentamethylene-ethyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] - amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. 40. The process according to claim 2, which is N- (1-carboxycyclohexyl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine or a salt thereof. characterized in that the appropriately substituted starting materials are used. 41. The process according to claim 1, which is (S) -N- (1-aminocarbonyl-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl). -biphenyl-4-ylmethyl] -amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. 42. The process of claim 1, wherein said (S) -N- (lacarboxy-2-methylprop-1-yl) -N- (5-oxopent-1-en-5-yl) N- [2'- (1H-Tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine or a salt thereof, characterized in that the appropriately substituted starting materials are used. 43. A process for the preparation of a pharmaceutical composition having an antihypertensive effect, comprising the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 25, 41 and 42, wherein R _{b is} R ₂ , R ₃ , The substituents X ₃ , X ₂ , X ₃ and ring A are as defined in the claims, known in the art, alone or in combination with excipients, binders, lubricants and other excipients used in the preparation of medicaments, optionally other similar active ingredients. such as a dragee, suppository, emulsion, solution for injection, suspension for injection or other known dosage form. 44. A process for the preparation of a medicament having an antihypertensive effect, comprising the steps of: 2, 9, 11, 13, 14, 17, 21, 24, 29, 30 and 32-40. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, wherein R 1, R ₂ , R ₃ , X ₁ , X ₂ , X ₃ and ring A substituents are as defined in the claims, known per se, or tablets, capsules, pills, dragees, suppositories, emulsion, in32, in combination with carriers, binders, lubricants, and other excipients, optionally The injection solution, suspension for injection or other known dosage form is prepared. 45. A process for the preparation of a medicament having an antihypertensive effect, comprising: 3-8., 10, 12, 15, 16, 18-20, 22, 23, 26-28. and a compound of formula or a pharmaceutically acceptable salt thereof described in any of 31. 5 formula (I) wherein _{Rb R2, R3,} X _b X _2, X _3, and the substituents on Ring A of the claims cited defined, in known manner, per se or in the form of tablets, capsules, pills, dragees, suppositories, emulsions, solution for injection, suspension for injection or other known forms of the drug, in combination with carriers, excipients, lubricants and other auxiliaries which may be used in the manufacture of medicaments.